U.S. patent application number 09/936566 was filed with the patent office on 2003-05-01 for human chymase inhibitors.
Invention is credited to Matsumoto, Yoshiyuki, Mizuno, Tsuyoshi, Saitou, Hiroshi, Tsuchiya, Naoki.
Application Number | 20030083315 09/936566 |
Document ID | / |
Family ID | 26583614 |
Filed Date | 2003-05-01 |
United States Patent
Application |
20030083315 |
Kind Code |
A1 |
Tsuchiya, Naoki ; et
al. |
May 1, 2003 |
Human chymase inhibitors
Abstract
The present invention provides a benzimidazole derivative or
its. pharmaceutically permissible salt expressed by the following
formula (1). Further, the present invention provides a human
chymase activity inhibitor containing the substance as an active
ingredient. 1 (the ring marked with A expresses a pyridline ring or
a benzene ring; X.sup.1 and X.sup.2 are each a hydrogen atom, a
halogen atom, a trihalomethyl group, a cyano group, a substituted
or unsubstituted alkyl group, a substituted or unsubstituted alkoxy
group, or the like; B is a substituted or unsubstituted alkylene
group, or the like; E is --COOR.sup.4 or the like; G is a
substituted or unsubstituted alkylene group; J is a substituted or
unsubstituted alkyl group, or a substituted or unsubstituted aryl
group; and M is a sulfur atom, sulfoxidde, sulfone or the
like).
Inventors: |
Tsuchiya, Naoki; (Tokyo,
JP) ; Matsumoto, Yoshiyuki; (Tokyo, JP) ;
Saitou, Hiroshi; (Tokyo, JP) ; Mizuno, Tsuyoshi;
(Tokyo, JP) |
Correspondence
Address: |
Sughrue Mion Zinn
Macpeak & Seas
Suite
2100 Pennsylvania Avenue NW
Washington
DC
20037-3213
US
|
Family ID: |
26583614 |
Appl. No.: |
09/936566 |
Filed: |
September 14, 2001 |
PCT Filed: |
January 17, 2001 |
PCT NO: |
PCT/JP01/00272 |
Current U.S.
Class: |
514/80 ; 514/361;
514/381; 514/394; 548/113; 548/134; 548/254; 548/306.4 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 9/00 20180101; A61P 37/00 20180101; C07D 235/16 20130101; A61K
31/437 20130101; A61P 37/08 20180101; C07D 235/28 20130101; A61K
31/4184 20130101; A61P 3/14 20180101; A61P 43/00 20180101; A61P
29/00 20180101 |
Class at
Publication: |
514/80 ; 514/361;
514/381; 514/394; 548/306.4; 548/113; 548/134; 548/254 |
International
Class: |
A61K 031/675; A61K
031/433; A61K 031/4184 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 17, 2000 |
JP |
2000-007532 |
Jan 19, 2000 |
JP |
2000-010406 |
Claims
1. An inhibitor against human chymase activity containing a
benzimidazole derivative expressed by the following formula (1) or
its salt as an active ingredient, 12[in the formula (1), the ring
marked with A expresses a pyridine ring or a benzene ring; X.sup.1
and X.sup.2 are each at the same time or independently a hydrogen
atom, a halogen atom, a trihalomethyl group, a hydroxyl group, a
nitro group, a cyano group, CH.sub.2NH.sub.2, --CH.dbd.NR.sup.1,
--CH.dbd.NOR.sup.1 or --CONR.sup.1R.sup.2 (here, R.sup.1 and
R.sup.2 are each a hydrogen atom or a C.sub.1-4 alkyl group),
--COOR.sup.3 (here, R.sup.3 is a hydrogen atom or a C.sub.1-4 alkyl
group), a substituted or unsubstituted C.sub.1-6 normal, cyclic or
branched alkyl group, a substituted or unsubstituted C.sub.3-7
cycloalkyl group, a substituted or unsubstituted C.sub.1-6 normal
or branched alkoxyl group, a substituted or unsubstituted C.sub.1-6
normal or branched alkylthio group, a substituted or unsubstituted
C.sub.1-6 normal or branched alkylsulfonyl group or a substituted
or unsubstituted C.sub.1-6 normal or branched alkylsulfinyl group
{the substituent permissible to the groups is a halogen atom, a
hydroxyl group, a nitro group, a cyano group, an acyl group, a
trihalomethyl group, a trihalomethoxy group, a phenyl group, an oxo
group or a phenoxy group optionally substituted with one or more
halogen atoms, and the substituent may substitute singly or
plurally independently at arbitrary position(s)}; B is a
substituted or unsubstituted C.sub.1-6 normal, cyclic or branched
alkylene group or a substituted or unsubstituted C.sub.2-6 normal
or branched alkenylene group {the substituent permissible to the
groups is a halogen atom, a hydroxyl group, a nitro group, a cyano
group, a C.sub.1-6 normal or branched alkoxyl group (including the
case where adjacent two groups form an acetal bonding), a C.sub.1-6
normal or branched alkylthio group, a C.sub.1-6 normal or branched
alkylsulfonyl group, a C.sub.1-6 normal or branched acyl group, a
C.sub.1-6 normal or branched acylamino group, a trihalomethyl
group, a trihalomethoxy group, a phenyl group, an oxo group or a
phenoxy group optionally substituted with one or more halogen
atoms, and the substituent may substitute singly or plurally
independently at arbitrary position(s) of the alkylene group or an
alkenylene group; between atoms, the alkylene group or alkenylene
group optionally contains one or more of --O--, --S--, --SO.sub.2--
or --NR.sup.4--, but this atom or atomic group does not bond
directly to the M, and here R.sup.4 is a hydrogen atom or a
C.sub.1-6 normal or branched alkyl group}; E expresses
--COOR.sup.4, --SO.sub.3R.sup.4, --CONHR.sup.5,
--SO.sub.2NHR.sup.4, --PO(OR.sup.6).sub.2, a tetrazol-5-yl group, a
5-oxo-1,2,4-oxadiazol-3-yl group or a 5-oxo-1,2,4-thiadiazol-3-yl
group (here, R.sup.4 is similarly defined as above; R.sup.5 is a
hydrogen atom, a cyano group, or a C.sub.1-6 normal or branched
alkyl group; R.sup.6 is a hydrogen atom, a C.sub.1-6 normal or
branched alkyl group, or trifluoromethylsulfonyl group, or its
pharmaceutically permissible salt); G is a substituted or
unsubstituted C.sub.1-6 normal or branched alkylene group {between
atoms, the alkylene group optionally contains one or more of --O--,
--S--, --SO.sub.2-- or --NR.sup.4--, but this atom or atomic group
does not bond directly to the nitrogen atom of the imidazole ring
(R.sup.4 is similarly defined as above), and the substituent is a
halogen atom, a hydroxyl group, a nitro group, a cyano group, a
C.sub.1-6 normal or branched alkoxyl group (including the case
where adjacent two groups form an acetal bonding), a trihalomethyl
group, a trihalomethoxy group, a phenyl group or an oxo group}; J
is a substituted or unsubstituted C.sub.1-6 normal, cyclic or
branched alkyl group, a substituted or unsubstituted C.sub.4-10
aryl group {the substituent permissible to the groups is a halogen
atom, a hydroxyl group, a nitro group, a cyano group, --COOR.sup.7
(here, R.sup.7 is a hydrogen atom or a C.sub.1-4 alkyl group), a
C.sub.1-6 normal, cyclic or branched alkyl group, a C.sub.1-6
normal or branched alkoxyl group (including the case where adjacent
two groups form an acetal bonding), a C.sub.1-6 normal or branched
alkylthio group, a C.sub.1-6 normal or branched alkylsulfonyl
group, a C.sub.1-6 normal or branched alkylsulfinyl group, a
C.sub.1-6 acyl group, a C.sub.1-6 normal or branched acylamino
group, a trihalomethyl group, a trihalomethoxy group, a phenyl
group, an oxo group, or a phenoxy group optionally substituted with
one or more halogen atoms; the substituent may substitute singly or
plurally independently at arbitrary position(s) of the alkyl group
or aryl group; and the substituent is further optionally
substituted with a halogen atom, a hydroxyl group, a nitro group, a
cyano group, an acyl group, a trihalomethyl group, a phenyl group,
an oxo group or a phenoxy group optionally substituted with a
halogen atom}; and M is a sulfur atom, a sulfinyl group, a sulfonyl
group, a single bond or --CR.sup.8R.sup.9-- (here, R.sup.8 and
R.sup.9 are each at the same time or independently a hydrogen atom
or a C.sub.1-4 alkyl group)].
2. An inhibitor against human chymase activity set forth in claim 1
wherein the ring marked with A in the above formula (1) is a
benzene ring.
3. An inhibitor against human chymase activity set forth in claim 1
wherein the ring marked with A in the above formula (1) is a
pyridine ring.
4. An inhibitor against human chymase activity set forth in one out
of claims 1 to 3 wherein X.sup.1 and X.sup.2 in the above formula
(1) are each at the same time or independently a hydrogen atom, a
halogen atom, a trihalomethyl group, a cyano group, a substituted
or unsubstituted C.sub.1-3 normal or branched alkyl group, a
substituted or unsubstituted C.sub.1-3 normal or branched alkoxyl
group, or a substituted or unsubstituted C.sub.1-3 normal or
branched alkylthio group.
5. An inhibitor against human chymase activity set forth in one out
of claims 1 to 4 wherein J in the above formula (1) is a group
described in the following formula (2) or (3), 13[here, X.sup.3,
X.sup.4 and X.sup.5 are each at the same time or independently a
hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a
cyano group, a trihalomethyl group, a trihalomethoxy group,
--COOR.sup.7 (here, R.sup.7 is a hydrogen atom or a C.sub.1-4 alkyl
group), a substituted or unsubstituted C.sub.1-3 normal or branched
alkyl group, a substituted or unsubstituted C.sub.1-3 normal or
branched alkoxyl group, a substituted or unsubstituted C.sub.1-3
normal or branched alkylthio group, a substituted or unsubstituted
C.sub.1-3 normal or branched alkylsulfonyl group, or a substituted
or unsubstituted C.sub.1-3 normal or branched alkylsulfinyl group;
there is no limitation regarding the substitution positions of
X.sup.3, X.sup.4 and X.sup.5 on the benzene ring or the naphthalene
ring].
6. An inhibitor against human chymase activity set forth in one out
of claims 1 to 5 wherein M in the above-mentioned formula (1) is a
sulfur atom.
7. An inhibitor against human chymase activity set forth in one out
of claims 1 to 6 wherein B in the above-mentioned formula (1) is a
substituted or unsubstituted C.sub.1-6 normal, cyclic or branched
alkylene group.
8. An inhibitor against human chymase activity set forth in one out
of claims 1 to 7 wherein G in the above-mentioned formula (1) is
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2CO--,
--CH.sub.2CH.sub.2O--, --CH.sub.2CONH--, --CO--, --SO.sub.2--,
--CH.sub.2SO.sub.2--, --CH.sub.2S-- or --CH.sub.2CH.sub.2S-- (J
bonds to the right side of said group).
9. An inhibitor against human chymase activity set forth in one out
of claims 1 to 8 wherein E in the above-mentioned formula (1) is
--COOH.
10. A benzimidazole derivative expressed by the following formula
(4) or its pharmaceutically permissible salt, 14[in the formula
(4), the definitions of the ring marked with A, and X.sup.1,
X.sup.2, B, E, G, J and M are same as those in the above formula
(1); however, excepting the case where at least one of X.sup.1 and
X.sup.2 is a cyano group, --CH.sub.2NH.sub.2, --CH.dbd.NR.sup.1,
--CH.dbd.NOR.sup.1 or --CONR.sup.1R.sup.2 (here, R.sup.1 and
R.sup.2 are each a hydrogen atom or a C.sub.1-4 alkyl group), J
expresses only a substituted naphthalene ring].
11. A benzimidazole derivative or its pharmaceutically permissible
salt set forth in claim 10 wherein X.sup.1 and X.sup.2 in the above
formula (4) are each a hydrogen atom, a cyano group,
--CH.sub.2NH.sub.2, --CH.dbd.NR.sup.1, --CH.dbd.NOR.sup.1 or
--CONR.sup.1R.sup.2 (here, R.sup.1 and R.sup.2 are each a hydrogen
atom or a C.sub.1-4 alkyl group; X.sup.1 and X.sup.2 are not
hydrogen at the same time).
12. A benzimidazole derivative or its pharmaceutically permissible
salt set forth in claim 10 wherein X.sup.1 and X.sup.2 in the above
formula (4) are each at the same time or independently a hydrogen
atom, a halogen atom, a trihalomethyl group, a hydroxyl group, a
nitro group, --CH--NR.sup.1 (here, R.sup.1 is a hydrogen atom or a
C.sub.1-4 alkyl group), --COOR.sup.8 (here, R.sup.3 is a hydrogen
atom or a C.sub.1-4 alkyl group), a substituted or unsubstituted
C.sub.1-6 normal, cyclic or branched alkyl group, a substituted or
unsubstituted C.sub.3-7 cycloalkyl, a substituted or unsubstituted
C.sub.1-6 normal or branched alkoxyl group, a substituted or
unsubstituted C.sub.1-6 normal or branched alkylthio group, a
substituted or unsubstituted C.sub.1-6 normal or branched
alkylsulfonyl group or a substituted or unsubstituted C.sub.1-6
normal or branched alkylsulfinyl group {the substituent permissible
to the groups is a halogen atom, a hydroxyl group, a nitro group, a
cyano group, an acyl group, a trihalomethyl group, a trihalomethoxy
group, a phenyl group, an oxo group or a phenoxy group optionally
substituted with one or more halogen atoms, and the substituent may
substitute singly or plurally independently at arbitrary
position(s)}.
13. A benzimidazole derivative or its pharmaceutically permissible
salt set forth in claim 10 wherein X.sup.1 and X.sup.2 in the above
formula (4) are each a hydrogen atom or a cyano group (here,
X.sup.1 and X.sup.2 can not be hydrogen toms at the same time).
14. A benzimidazole derivative or its pharmaceutically permissible
salt set forth in one out of claims 10 to 13 wherein M in the above
formula (4) is a sulfur atom.
15. A benzimidazole derivative or its pharmaceutically permissible
salt set forth in one out of claims 10 to 14 wherein B in the above
formula (4) is a substituted or unsubstituted C.sub.1-6 normal,
cyclic or branched alkylene group.
16. A benzimidazole derivative or its pharmaceutically permissible
salt set forth in one out of claims 10 to 15 wherein J in the above
formula (4) is a group expressed by the following formula (2) or
(3), 15[here, X.sup.3, X.sup.4 and X.sup.5 are each at the same
time or independently a hydrogen atom, a halogen atom, a hydroxyl
group, a nitro group, a cyano group, a trihalomethyl group, a
trihalomethoxy group, --COOR.sup.7 (here, R.sup.7 is a hydrogen
atom or a C.sub.1-4 alkyl group), a substituted or unsubstituted
C.sub.1-3 normal or branched alkyl group, a substituted or
unsubstituted C.sub.1-3 normal or branched alkoxyl group, a
substituted or unsubstituted C.sub.1-3 normal or branched alkylthio
group, a substituted or unsubstituted C.sub.1-3 normal or branched
alkylsulfonyl group, or a substituted or unsubstituted C.sub.1-3
normal or branched alkylsulfinyl group; there is no limitation
regarding the substitution positions of X.sup.3, X.sup.4 and
X.sup.5 on the benzene ring or the naphthalene ring].
17. A benzimidazole derivative or its pharmaceutically permissible
salt set forth in one out of claims 10 to 16 wherein G in the above
formula (4) is --CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2CO--,
--CH.sub.2CH.sub.2O--, CH.sub.2CONH--, --CO--, --SO.sub.2--,
-0CH.sub.2SO.sub.2--, --CH.sub.2S-- or --CH.sub.2CH.sub.2S-- (J
bonds to the right side of said group).
18. A benzimidazole derivative or its pharmaceutically permissible
salt set forth in one out of claims 10 to 17 wherein E in the above
formula (4) is COOH.
19. A pharmaceutical composition consisting of a benzimidazole
derivative and/or its pharmaceutically permissible salt set forth
in one out of claims 10 to 18, and a pharmaceutically permissible
carrier.
20. A chymase activity inhibitor set forth in one out of claims 1
to 9 whose targeting disease is an inflammatory disease, an allergy
disease, a respiratory disease, a cardiovascular disease or a
bone/cartridge metabolic disease.
21. A human chymase activity inhibitor set forth in claim 20 which
is a preventing agent or a treating agent of a disease.
Description
TECHNICAL FIELD
[0001] The present invention relates to a human chymase inhibitor
useful as a medicine. More specifically, the invention relates to a
new benzimidazole derivative useful as an active ingredient of an
inhibitor against human chymase activity.
BACKGROUND ART
[0002] A chymase exists in a granule of a mast cell, and it is one
of neutral proteinases and deeply relates to the various vital
reactions to which the mast cell relates. For example, there are
many reports such as the acceleration of degranulation from a mast
cell, the activation of interleukin-1 .beta. (IL-1 .beta.), the
activation of matrix protease, the degradation of fibronectin or
IV-type collagen, the acceleration of release of transforming
growth factor-.beta. (TGF-.beta.), the activation of substance-P or
vathoactive intestinal polypeptide (VIP), the conversion of
angiotensin (Ang) I to Ang II, and the conversion of endothelin.
From the above mentioned things, the inhibitor against the activity
of said chymase is considered to be promising as a compound
applicable to a preventing agent and/or treating agent for a
respiratory disease such as bronchial asthma; an
inflammatory/allergy disease such as allergic rhinitis, atopic
dermatitis or urticaria; a cardiovascular disease such as
sclerosing vascular lesion, intravascular stenosis, peripheral
circulatory disorder, kidney failure or cardiac failure; a
bone/cartridge metabolic disease such as rheumatism or
osteoarthritis; or the like.
[0003] Heretoforth, as chymase activity inhibitors, a triazine
derivative (JP-A 8-208654) (JP-A means Japanese Unexamined Patent
Publication), a hydantoin derivative (JP-A 9-31061), an
imidazolidine derivative (International Patent Publication
WO96/04248), a quinazoline derivative (International Patent
Publication WO97/11941), a heterocyclic amido derivative
(International Patent Publication WO96/33974) and the like have
been known.
[0004] However, regarding the triazine derivative, the inhibiting
activity was studied by using a rat chymase, and the inhibiting
activity against a human chymase is unclear. Regarding the
hydantoin derivative, the inhibiting activity against a human
chymase was investigated, but the activity is overall weak and
insufficient. Regarding the imidazolidine derivative, there is the
high possibility that it is an irreversible inhibitor (suicide
substrate) of a chymase judging from its chemical structure.
Further, all the structures of the abovementioned substances are
widely different from the structures of benzimidazole derivatives
of the present description.
[0005] On the other hand, as the relevant technology of the
benzimidazole derivative of the present invention, there are
benzimidazole derivatives described in U.S. Pat. Nos. 5,021,443,
5,124,336 and 5,128,339. However, there is neither description nor
suggestion regarding compounds having a cyano group,
--CH.sub.2NH.sub.2, --CH.dbd.NR.sup.1 or CONR.sup.1R.sup.2 (R.sup.1
and R.sup.2 are each a hydrogen atom or a C.sub.1-4 alkyl group) at
the position of 4, 5, 6 or 7 in a benzimidazole skeleton. Further,
said patent publications describe only antagonists against a
thromboxane receptor, and there is neither description nor
suggestion on an inhibiting activity against a human chymase.
DISCLOSURE OF THE INVENTION
[0006] It is an object of the present invention to provide an
inhibitor against human chymase activity containing a benzimidazole
derivative as the active ingredient and useful for clinical
applications.
[0007] Further, the object of the present invention is to provide a
new benzimidazole derivative or its pharmaceutically permissible
salt to be the active ingredient.
[0008] The inventors of the present invention repeatedly pursued
zealous studies in order to achieve the abovementioned objects, and
found that the imidazole derivative expressed by the following
formula (1) or its salt has an inhibiting activity selectively
against a human chymase in spite that it is completely different in
its structure from a serine proteinase inhibitor, which has been
heretofore reported.
[0009] That is, the present invention provides an inhibitor against
human chymase activity containing a benzimidazole derivative
expressed by the following formula (1) or its salt as the active
ingredient and useful for clinical applications. 2
[0010] [in the formula (1), the ring marked with A expresses a
pyridine ring or a benzene ring;
[0011] X.sup.1 and X.sup.2 are each at the same time or
independently a hydrogen atom, a halogen atom, a trihalomethyl
group, a hydroxyl group, a nitro group, a cyano group,
--CH.sub.2NH.sub.2, --CH.dbd.NR.sup.1, CH.dbd.NOR.sup.1 or
--CONR.sup.1R.sup.2 (here, R.sup.1and R.sup.2 are each a hydrogen
atom or a C.sub.1-4 alkyl group), --COOR.sup.3 (here, R.sup.3 is a
hydrogen atom or a C.sub.1-4 alkyl group), a substituted or
unsubstituted C.sub.1-6 normal, cyclic or branched alkyl group, a
substituted or unsubstituted C.sub.3-7 cycloalkyl group, a
substituted or unsubstituted C.sub.1-6 normal or branched alkoxyl
group, a. substituted or unsubstituted C.sub.1-6 normal or branched
alkylthio group, a substituted or unsubstituted C.sub.1-6 normal or
branched alkylsulfonyl group, or a substituted or unsubstituted
C.sub.1-6 normal or branched alkylsulfinyl group {the substituent
permissible to the groups is a halogen atom, a hydroxyl group, a
nitro group, a cyano group, an acyl group, a trihalomethyl group, a
trihalomethoxy group, a phenyl group, an oxo group or a phenoxy
group optionally substituted with one or more halogen atoms, and
the substituent may substitute singly or plurally independently at
arbitrary position(s)};
[0012] B is a substituted or unsubstituted C.sub.1-6 normal, cyclic
or branched alkylene group or a substituted or unsubstituted
C.sub.2-6 normal or branched alkenylene group {the substituent
permissible to the groups is a halogen atom, a hydroxyl group, a
nitro group, a cyano group, a C.sub.1-6 normal or branched alkoxyl
group (including the case where adjacent two groups form an acetal
bonding), a C.sub.1-6 normal or branched alkylthio group, a
C.sub.1-6 normal or branched alkylsulfonyl group, a C.sub.1-6
normal or branched acyl group, a C.sub.1-6 normal or branched
acylamino group, a trihalomethyl group, a trihalomethoxy group, a
phenyl group, an oxo group or a phenoxy group optionally
substituted with one or more halogen atoms, and the substituent may
substitute singly or plurally independently at arbitrary
position(s) of the alkylene group or an alkenylene group; between
atoms, the alkylene group or alkenylene group optionally contains
one or more of --O--, --S--, --SO.sub.2-- or --NR.sup.4--, but said
atom or atomic group does not bond directly to the M, and here
R.sup.4 is a hydrogen atom or a C.sub.1-6 normal or branched alkyl
group};
[0013] E expresses --COOR.sup.4, --SO.sub.3R.sup.4, --CONHR.sup.5,
--SO.sub.2NHR.sup.4, --PO(OR.sup.6).sub.2, a tetrazol-5-yl group, a
5-oxo-1,2,4-oxadiazol-3-yl group or a 5-oxo-1,2,4-thiadiazol-3-yl
group (here, R.sup.4 is similarly defined as above; R.sup.6 is a
hydrogen atom, a cyano group, or a C.sub.1-6 normal or branched
alkyl; Rr is a hydrogen atom, a C.sub.1-6 normal or branched alkyl
group, or a trifluoromethylsulfonyl group, or its pharmaceutically
permissible salt);
[0014] G is a substituted or unsubstituted C.sub.1-6 normal or
branched alkylene group {between atoms, the alkylene group
optionally contains one or more of --O--, --S--, --SO.sub.2-- or
--NR.sup.4--, but this atom or atomic group does not bond directly
to the nitrogen atom of the imidazole ring (R.sup.4 is similarly
defined as above), and the substituent is a halogen atom, a
hydroxyl group, a nitro group, a cyano group, a C.sub.1-6 normal or
branched alkoxyl group (including the case where adjacent two
groups form an acetal bonding), a trihalomethyl group, a
trihalomethoxy group, a phenyl group or an oxo group};
[0015] J is a substituted or unsubstituted C.sub.1-6 normal, cyclic
or branched alkyl group, a substituted or unsubstituted C.sub.4-10
aryl group {the substituent permissible to the groups is a halogen
atom, a hydroxyl group, a nitro group, a cyano group, --COOR.sup.7
(here, R.sup.7 is a hydrogen atom or a C.sub.1-4 alkyl group), a
C.sub.1-6 normal, cyclic or branched alkyl group, a C.sub.1-6
normal or branched alkoxyl group (including the case where adjacent
two groups form an acetal bonding), a C.sub.1-6 normal or branched
alkylthio group, a C.sub.1-6 normal or branched alkylsulfonyl
group, a C.sub.1-6 normal or branched alkylsulfinyl group, a
C.sub.1-6 acyl group, a C.sub.1-6 normal or branched acylamino
group, a trihalomethyl group, a trihalomethoxy group, a phenyl
group, an oxo group, or a phenoxy group optionally substituted with
one or more halogen atoms; the substituent may substitute singly or
plurally independently at arbitrary position(s) of the alkyl group
or aryl group; and the substituent is further optionally
substituted with a halogen atom, a hydroxyl group, a nitro group, a
cyano group, an acyl group, a trihalomethyl group, a phenyl group,
an oxo group or a phenoxy group optionally substituted with a
halogen atom}; and
[0016] M is a sulfur atom, a sulfinyl group, a sulfonyl group, a
single bond or --CR.sup.8R.sup.9-- (here, R.sup.8 and R.sup.9 are
each at the same time or independently a hydrogen atom or a
C.sub.1-4 alkyl group)].
[0017] Here, a part of the compounds expressed by the above formula
(1) are new compounds, and the present invention also provides the
imidazole derivatives like this or their salts.
BEST MODE FOR CARRYING OUT THE INVENTION
[0018] The substituents of the compound expresses by the above
formula (1) of the present invention are defined as follows:
[0019] The ring marked with A expresses a pyridine ring or a
benzene ring.
[0020] X.sup.1 and X.sup.2 are each at the same time or
independently a hydrogen atom, a halogen atom, a trihalomethyl
group, a hydroxyl group, a nitro group, a cyano group,
--CH.sub.2N.sub.2, --CH--NR.sup.1, --CH.dbd.NOR.sup.1 or
--CONR.sup.1R.sup.2 (here, R.sup.1 and R.sup.2 are each a hydrogen
atom or a C.sub.1-4 alkyl group), --COOR.sup.3 (here, R.sup.3 is a
hydrogen atom or a C.sub.1-4 alkyl group), a substituted or
unsubstituted C.sub.1-6 normal, cyclic or branched alkyl group, a
substituted or unsubstituted C.sub.3-7 cycloalkyl group, a
substituted or unsubstituted C.sub.1-6 normal or branched alkoxyl
group, a substituted or unsubstituted C.sub.1-6 normal or branched
alkylthio group, a substituted or unrubstituted C.sub.1-6 normal or
branched alkylsulfonyl group, or a substituted or unsubstituted
C.sub.1-6 normal or branched alkylsulfinyl group.
[0021] The halogen atom is an iodine atom, a fluorine atom, a
chlorine atom or a bromine atom, and preferably a fluorine atom or
a chlorine atom. The trihalomethyl group is specifically a
trifluoromethyl group, a tribromomethyl group or a trichloromethyl
group, and preferably a trifluoromethyl group. The unsubstituted
C.sub.1-6 alkyl group is specifically a methyl group, an ethyl
group, a n- or i-propyl group or a cyclohexyl group, and preferably
a methyl group or an ethyl group. The further preferable example is
a methyl group. The unsubstituted C.sub.1-6 alkoxyl group is
specifically a methoxy group, an ethoxy group, or a n- or i-propoxy
group, and preferably a methoxy group. The unsubstituted C.sub.1-6
alkylthio group is specifically a methylthio group, an ethylthio
group, or a n- or i-propylthio group, and preferably a methylthio
group. The unsubstituted C.sub.1-6 normal or branched alkylsulfonyl
group is specifically a methylsulfonyl group, an ethylsulfonyl
group, or a n- or i-propylsulfonyl group, and preferably a
methylsulfonyl group. The unsubstituted C.sub.1-6 normal or
branched alkylsulfinyl group is specifically a methylsulfinyl
group, an ethylsulfinyl group, or a n- or i-propylsulfinyl group,
and preferably a methylsulfinyl group.
[0022] The substituent permissible to the groups is a halogen atom,
a hydroxyl group, a nitro group, a cyano group, an acyl group, a
trihalomethyl group, a trihalomethoxy group, a phenyl group, an oxo
group or a phenoxy group optionally substituted with one or more
halogen atoms, and the substituent may substitute singly or
plurally independently at arbitrary position(s). Especially
preferable substituent out of them is a halogen atom, a hydroxyl
group, a cyano group or an acyl group, and further preferable
substituent is a fluorine atom, a chlorine atom or a cyano
group.
[0023] R.sup.1and R.sup.2 are each a hydrogen atom or a C.sub.1-4
alkyl group, and specifically a hydrogen atom, a methyl group, an
ethyl group, a n- or i-propyl group, a n-, i-, s- or t-butyl group.
They are each preferably a hydrogen atom, a methyl group or an
ethyl group, and more preferably a hydrogen atom or a methyl
group.
[0024] Especially, X.sup.1 and X.sup.2 are each preferably a
hydrogen atom, a halogen atom, a trihalomethyl group, a cyano
group, a substituted or unsubstituted C.sub.1-3 normal or branched
alkyl group, a substituted or unsubstituted C.sub.1-3 normal or
branched alkoxyl group or a substituted or unsubstituted C.sub.1-3
normal or branched alkylthio group. More preferably, they are each
a hydrogen atom, a fluorine atom, a chlorine atom, a
trifluoromethyl group, a cyano group, an unsubstituted C.sub.1-3
normal or branched alkyl group, an unsubstituted C.sub.1-3 normal
or branched alkoxyl group, or an unsubstituted C.sub.1-3 normal or
branched alkylthio group. Further preferably, they are each a
hydrogen atom, a chlorine atom, a fluorine atom, a trifluoromethyl
group, a cyano group, a methoxy group, an ethoxy group, a methyl
group, an ethyl group or a methylthio group.
[0025] Regarding the positions of substitution of X.sup.1 and
X.sup.2, there is no limitation; however, when the ring marked with
A in the formula (1) is a benzene ring, the combination of the
5-position and the 6-position of the benzimidazole ring is the most
preferable.
[0026] B is a substituted or unsubstituted C.sub.1-6 normal, cyclic
or branched alkylene group, or a substituted or unsubstituted
C.sub.2-6 normal or branched alkenylene group. The unsubstituted
C.sub.1-6 normal, cyclic or branched alkylene group is a methylene
group, an ethylene group, a n- or i-propylene group, a
2,2-dimethylpropylene group, a n-, i- or t-butylene group, a
1,1-dimethylbutylene group, a n-pentylene group, a cyclohexylene
group, or the like. A preferable example among them is an ethylene
group, a n-propylene group or a 2,2-dimethylpropylene group, and an
especially preferable example is a n-propylene group. The
unsubstituted C.sub.2-6 normal or branched alkenylene group is a
vinylene group, a vinylidene group, an allylene group or the
like.
[0027] Between atoms, such alkylene or alkenylene group may contain
one or more of --O--, --S--, --SO.sub.2-- or --NR.sup.4-- (here,
R.sup.4 is a hydrogen atom or a C.sub.1-6 normal or branched alkyl
group), but said atom or atomic group does not bond directly to the
M. Specifically, an example of the group formed by this is a group
in which said atom or atomic group is inserted into between atoms
of an ethylene group, a n-propylene group, or a n- or t-butylene
group. Further specifically, it is --CH.sub.2OCH.sub.2--,
--CH.sub.2OCH.sub.2CH.sub.2--, --CH.sub.2--CH.sub.2--,
--CH.sub.2SCH.sub.2CH.sub.2--, --CH.sub.2SO.sub.2CH.sub.2--,
--CH.sub.2SO.sub.2CH.sub.2CH.sub.2--, --CH.sub.2NR.sup.4CH.sub.2--,
--CHNR.sup.4CH.sub.2CH.sub.2-- or the like, and it is especially
preferably --CH.sub.2OCH.sub.2--, --CH.sub.2SCH.sub.2-- or
--CH.sub.2SO.sub.2CH.sub.2.
[0028] The substituent permissible to the groups is a halogen atom,
a hydroxyl group, a nitro group, a cyano group, a C.sub.1-6 normal
or branched alkoxyl group including the case where adjacent two
groups form an acetal bonding), a C.sub.1-6 normal or branched
alkylthio group, a C.sub.1-6;normal or branched alkylsulfonyl
group, a C.sub.1-6 normal or branched acyl group, a C.sub.1-6
normal or branched acylamino group, a trihalomethyl group, a
trihalomethoxy group, a phenyl group, an oxo group or a phenoxy
group optionally substituted with one or more halogen atoms. The
substituent may each substitute singly or plurally independently at
arbitrary position(s) of the alkylene or alkenylene group.
[0029] Said halogen atom is a fluorine atom, a chlorine atom, a
bromine atom or an iodine atom. It is preferably a fluorine atom or
a chlorine atom. Said C.sub.1-6 normal or branched alkoxyl group is
specifically a methoxy group, an ethoxy group, a n- or i-propyloxy
group, a n-, i-, s- or t-butoxy group, or the like; it is
preferably a methoxy group or an ethoxy group; and it is further
preferably a methoxy group. Said C.sub.1-6 normal or branched
alkylthio group is specifically a methylthio group, an ethylthio
group, a n- or i-propylthio group, a n-, i-, s- or t-butylthio
group, or the like; it is preferably a methylthio group or an
ethylthio group; and it is further preferably a methylthio group.
Said C.sub.1-6 normal or branched alkylsulfonyl group is
specifically a methylsulfonyl group, an ethylsulfonyl group, a n-
or i-propylsulfonyl group, a n-, i-, s- or t-butylsulfonyl group,
or the like; it is preferably a methylsulfonyl group or an
ethylsulfonyl group; and it is further preferably a methylsulfonyl
group. Said C.sub.1-6 normal or branched acylamino group is
specifically an acetylamino group, an ethylcarbonylamino group, a
n- or i-propylcarbonylamino group, or the like; it is preferably an
acetylamino group or an ethylcarbonylamino group; and it is further
preferably an acetylamino group. Said trihalomethyl group is
specifically a trifluoromethyl group, a tribromomethyl group or a
trichloromethyl group; and it is preferably a trifluoromethyl
group.
[0030] Especially, B is preferably a substituted or unsubstituted
C.sub.1-6 normal, cyclic or branched alkylene group {between atoms,
the alkylene group optionally contains one or more of --O--, --S--,
--SO.sub.2-- or --NR.sup.4-- (here, NR.sup.4 is defined same as
above), but the atom or the atomic group does not bond directly to
the M}. More preferably, it is --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2C(--O)CH.sub.2--,
--CH.sub.2OCH.sub.2--, --CH.sub.2SCH.sub.2--,
--CH.sub.2S(.dbd.O)CH.sub.2--, --CH.sub.2CF2CH.sub.2--,
--CH.sub.2SO.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2C(CH.sub.3).sub.2CH.sub.2--,
--CH.sub.2SO.sub.2CH.sub.2CH.sub.2- --, --CH.sub.2C
(--O)CH.sub.2CH.sub.2--, --CH.sub.2C(.dbd.O)C(CH.sub.3).su-
b.2CH.sub.2-- or --CH.sub.2C(.dbd.O)C(.dbd.O)CH.sub.2--. Further
preferably, it is --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2C (.dbd.O)CH.sub.2--,
--CH.sub.2OCH.sub.2--, --CH.sub.2SCH.sub.2--,
--CH.sub.2S(.dbd.O)GCH.sub.2--, -GCH.sub.2CF.sub.2CH.sub.2--,
--CH.sub.2SO.sub.2CH.sub.2-- or
--CH.sub.2C(CH.sub.3).sub.2CH.sub.2--. Further more preferably, it
is --CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2C(CH.sub.3).sub.2CH.sub.2--. Especially preferably, it is
--CH.sub.2CH.sub.2CH.sub.2--.
[0031] E expresses --COOR.sup.4, --SO.sub.3R.sup.4, --CONHR.sup.5,
--SO.sub.2NHR.sup.4, --PO(OR.sup.6).sub.2, a tetrazol-5-yl group, a
5-oxo-1,2,4-oxadiazol-3-yl group, or a 5-oxo-1,2,4-thiadiazol-3-yl
group (here, R.sup.4 is a hydrogen atom or a C.sub.1-6 normal or
branched alkyl group; R.sup.5 is a hydrogen atom, a cyano group, or
a C.sub.1-6 normal or branched alkyl group; R.sup.6 is a hydrogen
atom, a C.sub.1-6 normal or branched alkyl group or a
trifluoromethylsulfonyl group, or a pharmaceutically permissible
salt of the groups).
[0032] Here, R.sup.4 is a hydrogen atom, a methyl group, an ethyl
group, a n- or i-propyl group, a n-, i-, s- or t-butyl group, or
the like. Preferably, it is a hydrogen atom, a methyl group or an
ethyl group. Especially preferably, it is a hydrogen atom. R.sup.5
is a hydrogen atom, a cyano group, a methyl group, an ethyl group,
a n- or i-propyl group, a n-, i-, s- or t-butyl group, or the like.
Preferably, it is a hydrogen atom, a methyl group or an ethyl
group. Especially preferably, it is a hydrogen atom.
[0033] Especially, E is preferably --COOR.sup.4, --SO.sub.3R.sup.4,
or a tetrazol-5-yl group. Further preferably, it is --COOR.sup.4.
Especially preferably, it is --COOH.
[0034] G is a substituted or unsubstituted C.sub.1-6 normal or
branched alkylene group. Between atoms, the alkylene group
optionally contains one or more of --O--, --S--, --SO.sub.2-- or
--NR.sup.4--, but this atom or atomic group does not bond directly
to the nitrogen atom of the imidazole ring. Further, R.sup.4 is
similarly defined as above. The permissible substituent to the
groups is a halogen atom, a hydroxyl group, a nitro group, a cyano
group, a C.sub.1-6 normal or branched alkoxyl group (including the
case where adjacent two groups form an acetal bonding), a
trihalomethyl group, a trihalomethoxy group, a phenyl group or an
oxo group.
[0035] Preferably, G is --CH.sub.2--, CH.sub.2CH.sub.2--,
--CH.sub.2CO--, --CH.sub.2CH.sub.2O--, --CH.sub.2CONH--, --CO--,
--SO.sub.2--, --CH.sub.2SO.sub.2--, --CH.sub.2S--,
--CH.sub.2CH.sub.2S-- or the like (J bonds to the right side of
said group). Preferably, it is --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CO-- or --CH.sub.2CH.sub.2O--. Further preferably, it is
--CH.sub.2--.
[0036] J is a substituted or unsubstituted C.sub.1-6 normal, cyclic
or branched alkyl group, or a substituted or unsubstituted
C.sub.4-10 aryl group. The unsubstituted C.sub.1-6 normal, cyclic
or branched alkyl group is a methyl group, an ethyl group, a n- or
i-propyl group, a n-, i-, s- or t-butyl group, a cyclopentyl group,
a cyclohexyl group, or the like.
[0037] The substituent permissible to the groups is a halogen atom,
a hydroxyl group, a nitro group, a cyano group, --COOR.sup.7 (here,
R.sup.7 is a hydrogen atom or a C.sub.1-4 alkyl group), a C.sub.1-6
normal, cyclic or branched alkyl group, a C.sub.1-6 normal or
branched alkoxyl group (including the case where adjacent two
groups form an acetal bonding), a C.sub.1-6 normal or branched
alkylthio group, a C.sub.1-6 normal or branched alkylsulfonyl
group, a C.sub.1-6 normal or branched alkylsulfinyl group, a
C.sub.1-6 normal or branched acyl group, a C.sub.1-6 normal or
branched acylamino group, a trihalomethyl group, a trihalomethoxy
group, a phenyl group, an oxo group, or a phenoxy group optionally
substituted with one or more halogen atoms. The substituents may
each substitute singly or plurally independently at arbitrary
position(s) of the alkyl group or aryl group. Further, the
substituent is optionally substituted with a halogen atom, a
hydroxyl group, a nitro group, a cyano group, an acyl group, a
trihalomethyl group, a phenyl group, an oxo group or a phenoxy
group optionally substituted with a halogen atom.
[0038] Especially, a preferable example of J is a substituted or
unsubstituted C.sub.4-10 aryl group. Specifically, a group
expressed by the following formula (2) or (3) is preferable. 3
[0039] [here, X.sup.3, X.sup.4 and X.sup.5 are each at the same
time or independently a hydrogen atom, a halogen atom, a hydroxyl
group, a nitro group, a cyano group, a trihalomethyl group, a
trihalomethoxy group, --COOR.sup.7 (here, R.sup.7 is a hydrogen
atom or a C.sub.1-4 alkyl group), a substituted or unsubstituted
C.sub.1-3 normal or branched alkyl group, a substituted or
unsubstituted C.sub.1-3 normal or branched alkoxyl group, a
substituted or unsubstituted C.sub.1-3 normal or branched alkylthio
group, a substituted or unsubstituted C.sub.1-3 normal or branched
alkylsulfonyl group, or a substituted or unsubstituted C.sub.1-3
normal or branched alkylsulfinyl group; and there is no limitation
regarding the substitution positions of X.sup.3, X.sup.4 and
X.sup.5 on the benzene ring or the naphthalene ring].
[0040] Said halogen atom is a fluorine atom, a chlorine atom, a
bromine atom or an iodine atom. Preferably, it is a fluorine atom
or a chlorine atom. The trihalomethyl group is preferably a
trifluoromethyl group. The trihalomethoxy group is preferably a
trifluoromethoxy group. The unsubstituted C.sub.1-3 normal or
branched alkyl group is specifically a methyl group, an ethyl
group, or a n- or i-propyl group. The unsubstituted C.sub.1-3
normal or branched alkoxyl group is specifically a methoxy group,
an ethoxy group, or a n- or i-propyloxy group. The unsubstituted
C.sub.1-3 normal or branched alkylthio group is specifically a
methylthio group, an ethylthio group, or a n- or i-propylthio
group. The unsubstituted C.sub.1-3 normal or branched alkylsulfonyl
group is specifically a methylsulfonyl group, an ethylsulfonyl
group, or a n- or i-propylsulfonyl group. The uinsubstituted
C.sub.1-3 normal or branched alkylsulfinyl group is specifically a
methylsulfinyl group, an ethylsulfinyl group, or a n- or
i-propylsulfinyl group.
[0041] These substituents are optionally further substituted with a
halogen atom, a hydroxyl group, a nitro group, a cyano group, an
acyl group, a trihalomethyl group, a phenyl group, an oxo group or
a phenoxy group optionally substituted with a halogen atom.
[0042] Regarding the positions of substitution of X.sup.3, X.sup.4
and X.sup.5, there is no special limitation; however, in the above
formula (2), the combination of the 2-position and the 3-position,
or the combination of the 2-position and the 5-position is
preferable, and in the formula (3), the combination of the
4-position, the 7-position and the 8-position, the combination of
the 4-position, the 6-position and the 8-position, or the
combination of the 6-position, the 7-position and the 8-position is
preferable.
[0043] Especially, preferable examples of J include a
2-methylphenyl group, a 2-ethylphenyl group, a 3-trifluoromethyl
group, a 2-ethoxyphenyl group, a 3-methoxyphenyl group, a
2-chlorophenyl group, a 2trifluorophenyl group, a
2,3-methylenedioxyphenyl group, a 2-methyl-3-methoxyphenyl group, a
2-trifluoromethyl-3-methoxyphenyl group, a
2-methyl-3-trifluoromethoxyphenyl group, a 2,3-dimethylphenyl
group, a 2,3-dichlorophenyl group, a 2,3-dimethoxyphenyl group, a
2,5-dimethoxyphenyl group, a 2,5-dimethylphenyl group, a
2,5-dichlorophenyl group, a 2,5-ditrifluoromethylphenyl group, a
1-naphthyl group, a 2-naphthyl group, a 8-methyl-1-naphthyl group,
a 7-methyl-1-naphthyl group, a 6,8-dimethyl-1-naphthyl group and a
4,6,8-trimethyl-1-naphthyl group.
[0044] M is a sulfur atom, a sulfinyl group, a sulfonyl group, a
single bond or --CR.sup.8R.sup.9-- (here, R.sup.8 and R.sup.9 are
each at the same time or independently a hydrogen atom or a
C.sub.1-4 alkyl group).
[0045] R.sup.8 and R.sup.9 are each a hydrogen atom, a methyl
group, an ethyl group, a n- or i-propyl group, or a n-, i-, s- or
t-butyl group. They are preferably hydrogen atoms.
[0046] Especially, preferable example of M is a sulfur atom, a
sulfinyl group or a sulfonyl group. More preferably, M is a sulfur
atom.
[0047] Further, benzimidazole derivatives expressed by the
following formula (4) or their pharmaceutically permissible salts
out of the compounds expressed by the above formula (1) are new
compounds. 4
[0048] [in the formula (4), the definitions of the ring marked with
A, and X.sup.1, X.sup.2, B, E, G, J and M are same as those in the
above formula (1); however, excepting the cases where at least one
of X.sup.1 and X.sup.2 is a cyano group, --CH.sub.2NH.sub.2,
--CH.dbd.NR.sup.1, --CH.dbd.NOR.sup.1 or --CONR.sup.1R.sup.2 (here,
R.sup.1 and R.sup.2 are each a hydrogen atom or a C.sub.1-4 alkyl
group), J expresses only a substituted naphthalene ring].
[0049] Regarding the substituents of the compound expressed by the
above formula (4) of the present invention, the definitions and the
preferable groups of X.sup.1, X.sup.2, G, J, M, B and E are same as
those in the above formula (1).
[0050] Concrete examples of compounds expressed by the above
formula (1) are shown in the following tables. Yet, BI to Bil, and
J1 to J74 in the tables are groups shown in the following formulae.
In the formulae, the definitions of E and G are same as their
definitions shown above.
[0051] Yet, preferable compounds are those having the
above-mentioned preferable combinations of groups regarding
X.sup.1, X.sup.2, the ring marked with A, and B, G, J, B and E, and
not all of the compounds are shown in the tables. Further, the
following tables exemplify compounds in which the ring marked with
A is a benzene ring, but the situations can be considered to be
same also in the case where it is a pyridine ring. 5
1 (1) 6 Compound No. X.sup.1 X.sup.2 B E G J M 1 H H B3 COOH
CH.sub.2 J4 S 2 5-Me H B3 COOH CH.sub.2 J4 S 3 5-Et H B3 COOH
CH.sub.2 J4 S 4 5-F H B3 COOH CH.sub.2 J4 S 5 5-Cl H B3 COOH
CH.sub.2 J4 S 6 5-CF.sub.3 H B3 COOH CH.sub.2 J4 S 7 5-MeO H B3
COOH CH.sub.2 J4 S 8 5-EtO H B3 COOH CH.sub.2 J4 S 9 5-Me 6-Me B3
COOH CH.sub.2 J4 S 10 5-Et 6-Et B3 COOH CH.sub.2 J4 S 11 5-F 6-F B3
COOH CH.sub.2 J4 S 12 5-Cl 6-Cl B3 COOH CH.sub.2 J4 S 13 5-CF.sub.3
6-CF.sub.3 B3 COOH CH.sub.2 J4 S 14 5-MeO 6-MeO B3 COOH CH.sub.2 J4
S 15 5-EtO 6-EtO B3 COOH CH.sub.2 J4 S 16 H H B3 COOH CH.sub.2 J10
S 17 5-Me H B3 COOH CH.sub.2 J10 S 18 5-Et H B3 COOH CH.sub.2 J10 S
19 5-F H B3 COOH CH.sub.2 J10 S 20 5-Cl H B3 COOH CH.sub.2 J10 S 21
5-CF.sub.3 H B3 COOH CH.sub.2 J10 S 22 5-MeO H B3 COOH CH.sub.2 J10
S 23 5-EtO H B3 COOH CH.sub.2 J10 S 24 5-Me 6-Me B3 COOH CH.sub.2
J10 S 25 5-Et 6-Et B3 COOH CH.sub.2 J10 S 26 5-F 6-F B3 COOH
CH.sub.2 J10 S 27 5-Cl 6-Cl B3 COOH CH.sub.2 J10 S 28 5-CF.sub.3
6-CF.sub.3 B3 COOH CH.sub.2 J10 S 29 5-MeO 6-MeO B3 COOH CH.sub.2
J10 S 30 5-EtO 6-EtO B3 COOH CH.sub.2 J10 S 31 H H B3 COOH CH.sub.2
J16 S 32 5-Me H B3 COOH CH.sub.2 J16 S 33 5-Et H B3 COOH CH.sub.2
J16 S 34 5-F H B3 COOH CH.sub.2 J16 S 35 5-Cl H B3 COOH CH.sub.2
J16 S 36 5-CF.sub.3 H B3 COOH CH.sub.2 J16 S 37 5-MeO H B3 COOH
CH.sub.2 J16 S 38 5-EtO H B3 COOH CH.sub.2 J16 S 39 5-Me 6-Me B3
COOH CH.sub.2 J16 S 40 5-Et 6-Et B3 COOH CH.sub.2 J16 S 41 5-F 6-F
B3 COOH CH.sub.2 J16 S 42 5-Cl 6-Cl B3 COOH CH.sub.2 J16 S 43
5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J16 S 44 5-MeO 6-MeO B3 COOH
CH.sub.2 J16 S 45 5-EtO 6-EtO B3 COOH CH.sub.2 J16 S 46 H H B3 COOH
CH.sub.2 J18 S 47 5-Me H B3 COOH CH.sub.2 J18 S 48 5-Et H B3 COOH
CH.sub.2 J18 S 49 5-F H B3 COOH CH.sub.2 J18 S 50 5-Cl H B3 COOH
CH.sub.2 J18 S 51 5-CF.sub.3 H B3 COOH CH.sub.2 J18 S 52 5-MeO H B3
COOH CH.sub.2 J18 S 53 5-EtO H B3 COOH CH.sub.2 J18 S 54 5-Me 6-Me
B3 COOH CH.sub.2 J18 S 55 5-Et 6-Et B3 COOH CH.sub.2 J18 S 56 5-F
6-F B3 COOH CH.sub.2 J18 S 57 5-Cl 6-Cl B3 COOH CH.sub.2 J18 S 58
5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J18 S 59 5-MeO 6-MeO B3 COOH
CH.sub.2 J18 S 60 5-EtO 6-EtO B3 COOH CH.sub.2 J18 S 61 H H B3 COOH
CH.sub.2 J21 S 62 5-Me H B3 COOH CH.sub.2 J21 S 63 5-Et H B3 COOH
CH.sub.2 J21 S 64 5-F H B3 COOH CH.sub.2 J21 S 65 5-Cl H B3 COOH
CH.sub.2 J21 S 66 5-CF.sub.3 H B3 COOH CH.sub.2 J21 S 67 5-MeO H B3
COOH CH.sub.2 J21 S 68 5-EtO H B3 COOH CH.sub.2 J21 S 69 5-Me 6-Me
B3 COOH CH.sub.2 J21 S 70 5-Et 6-Et B3 COOH CH.sub.2 J21 S 71 5-F
6-F B3 COOH CH.sub.2 J21 S 72 5-Cl 6-Cl B3 COOH CH.sub.2 J21 S 73
5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J21 S 74 5-MeO 6-MeO B3 COOH
CH.sub.2 J21 S 75 5-EtO 6-EtO B3 COOH CH.sub.2 J21 S 76 H H B3 COOH
CH.sub.2 J38 S 77 5-Me H B3 COOH CH.sub.2 J38 S 78 5-Et H B3 COOH
CH.sub.2 J38 S 79 5-F H B3 COOH CH.sub.2 J38 S 80 5-Cl H B3 COOH
CH.sub.2 J38 S 81 5-CF.sub.3 H B3 COOH CH.sub.2 J38 S 82 5-MeO H B3
COOH CH.sub.2 J38 S 83 5-EtO H B3 COOH CH.sub.2 J38 S 84 5-Me 6-Me
B3 COOH CH.sub.2 J38 S 85 5-Et 6-Et B3 COOH CH.sub.2 J38 S 86 5-F
6-F B3 COOH CH.sub.2 J38 S 87 5-Cl 6-Cl B3 COOH CH.sub.2 J38 S 88
5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J38 S 89 5-MeO 6-MeO B3 COOH
CH.sub.2 J38 S 90 5-EtO 6-EtO B3 COOH CH.sub.2 J38 S 91 H H B3 COOH
CH.sub.2 J42 S 92 5-Me H B3 COOH CH.sub.2 J42 S 93 5-Et H B3 COOH
CH.sub.2 J42 S 94 5-F H B3 COOH CH.sub.2 J42 S 95 5-Cl H B3 COOH
CH.sub.2 J42 S 96 5-CF.sub.3 H B3 COOH CH.sub.2 J42 S 97 5-MeO H B3
COOH CH.sub.2 J42 S 98 5-EtO H B3 COOH CH.sub.2 J42 S 99 5-Me 6-Me
B3 COOH CH.sub.2 J42 S 100 5-Et 6-Et B3 COOH CH.sub.2 J42 S 101 5-F
6-F B3 COOH CH.sub.2 J42 S 102 5-Cl 6-Cl B3 COOH CH.sub.2 J42 S 103
5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J42 S 104 5-MeO 6-MeO B3
COOH CH.sub.2 J42 S 105 5-EtO 6-EtO B3 COOH CH.sub.2 J42 S 106 H H
B3 COOH CH.sub.2 J44 S 107 5-Me H B3 COOH CH.sub.2 J44 S 108 5-Et H
B3 COOH CH.sub.2 J44 S 109 5-F H B3 COOH CH.sub.2 J44 S 110 5-Cl H
B3 COOH CH.sub.2 J44 S 111 5-CF.sub.3 H B3 COOH CH.sub.2 J44 S 112
5-MeO H B3 COOH CH.sub.2 J44 S 113 5-EtO H B3 COOH CH.sub.2 J44 S
114 5-Me 6-Me B3 COOH CH.sub.2 J44 S 115 5-Et 6-Et B3 COOH CH.sub.2
J44 S 116 5-F 6-F B3 COOH CH.sub.2 J44 S 117 5-Cl 6-Cl B3 COOH
CH.sub.2 J44 S 118 5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J44 S 119
5-MeO 6-MeO B3 COOH CH.sub.2 J44 S 120 5-EtO 6-EtO B3 COOH CH.sub.2
J44 S 121 H H B3 COOH CH.sub.2 J63 S 122 5-Me H B3 COOH CH.sub.2
J63 S 123 5-Et H B3 COOH CH.sub.2 J63 S 124 5-F H B3 COOH CH.sub.2
J63 S 125 5-Cl H B3 COOH CH.sub.2 J63 S 126 5-CF.sub.3 H B3 COOH
CH.sub.2 J63 S 127 5-MeO H B3 COOH CH.sub.2 J63 S 128 5-EtO H B3
COOH CH.sub.2 J63 S 129 5-Me 6-Me B3 COOH CH.sub.2 J63 S 130 5-Et
6-Et B3 COOH CH.sub.2 J63 S 131 5-F 6-F B3 COOH CH.sub.2 J63 S 132
5-Cl 6-Cl B3 COOH CH.sub.2 J63 S 133 5-CF.sub.3 6-CF.sub.3 B3 COOH
CH.sub.2 J63 S 134 5-MeO 6-MeO B3 COOH CH.sub.2 J63 S 135 5-EtO
6-EtO B3 COOH CH.sub.2 J63 S 136 H H B3 COOH CH.sub.2 J4 C 137 5-Me
H B3 COOH CH.sub.2 J4 C 138 5-Et H B3 COOH CH.sub.2 J4 C 139 5-F H
B3 COOH CH.sub.2 J4 C 140 5-Cl H B3 COOH CH.sub.2 J4 C 141
5-CF.sub.3 H B3 COOH CH.sub.2 J4 C 142 5-MeO H B3 COOH CH.sub.2 J4
C 143 5-EtO H B3 COOH CH.sub.2 J4 C 144 5-Me 6-Me B3 COOH CH.sub.2
J4 C 145 5-Et 6-Et B3 COOH CH.sub.2 J4 C 146 5-F 6-F B3 COOH
CH.sub.2 J4 C 147 5-Cl 6-Cl B3 COOH CH.sub.2 J4 C 148 5-CF.sub.3
6-CF.sub.3 B3 COOH CH.sub.2 J4 C 149 5-MeO 6-MeO B3 COOH CH.sub.2
J4 C 150 5-EtO 6-EtO B3 COOH CH.sub.2 J4 C 151 H H B3 COOH CH.sub.2
J10 C 152 5-Me H B3 COOH CH.sub.2 J10 C 153 5-Et H B3 COOH CH.sub.2
J10 C 154 5-F H B3 COOH CH.sub.2 J10 C 155 5-Cl H B3 COOH CH.sub.2
J10 C 156 5-CF.sub.3 H B3 COOH CH.sub.2 J10 C 157 5-MeO H B3 COOH
CH.sub.2 J10 C 158 5-EtO H B3 COOH CH.sub.2 J10 C 159 5-Me 6-Me B3
COOH CH.sub.2 J10 C 160 5-Et 6-Et B3 COOH CH.sub.2 J10 C 161 5-F
6-F B3 COOH CH.sub.2 J10 C 162 5-Cl 6-Cl B3 COOH CH.sub.2 J10 C 163
5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J10 C 164 5-MeO 6-MeO B3
COOH CH.sub.2 J10 C 165 5-EtO 6-EtO B3 COOH CH.sub.2 J10 C 166 H H
B3 COOH CH.sub.2 J16 C 167 5-Me H B3 COOH CH.sub.2 J16 C 168 5-Et H
B3 COOH CH.sub.2 J16 C 169 5-F H B3 COOH CH.sub.2 J16 C 170 5-Cl H
B3 COOH CH.sub.2 J16 C 171 5-CF.sub.3 H B3 COOH CH.sub.2 J16 C 172
5-MeO H B3 COOH CH.sub.2 J16 C 173 5-EtO H B3 COOH CH.sub.2 J16 C
174 5-Me 6-Me B3 COOH CH.sub.2 J16 C 175 5-Et 6-Et B3 COOH CH.sub.2
J16 C 176 5-F 6-F B3 COOH CH.sub.2 J16 C 177 5-Cl 6-Cl B3 COOH
CH.sub.2 J16 C 178 5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J16 C 179
5-MeO 6-MeO B3 COOH CH.sub.2 J16 C 180 5-EtO 6-EtO B3 COOH CH.sub.2
J18 C 181 H H B3 COOH CH.sub.2 J18 C 182 5-Me H B3 COOH CH.sub.2
J18 C 183 5-Et H B3 COOH CH.sub.2 J18 C 184 5-F H B3 COOH CH.sub.2
J18 C 185 5-Cl H B3 COOH CH.sub.2 J18 C 186 5-CF.sub.3 H B3 COOH
CH.sub.2 J18 C 187 5-MeO H B3 COOH CH.sub.2 J18 C 188 5-EtO H B3
COOH CH.sub.2 J18 C 189 5-Me 6-Me B3 COOH CH.sub.2 J18 C 190 5-Et
6-Et B3 COOH CH.sub.2 J18 C 191 5-F 6-F B3 COOH CH.sub.2 J18 C 192
5-Cl 6-Cl B3 COOH CH.sub.2 J18 C 193 5-CF.sub.3 6-CF.sub.3 B3 COOH
CH.sub.2 J18 C 194 5-MeO 6-MeO B3 COOH CH.sub.2 J18 C 195 5-EtO
6-EtO B3 COOH CH.sub.2 J18 C 196 H H B3 COOH CH.sub.2 J21 C 197
5-Me H B3 COOH CH.sub.2 J21 C 198 5-Et H B3 COOH CH.sub.2 J21 C 199
5-F H B3 COOH CH.sub.2 J21 C 200 5-Cl H B3 COOH CH.sub.2 J21 C 201
5-CF.sub.3 H B3 COOH CH.sub.2 J21 C 202 5-MeO H B3 COOH CH.sub.2
J21 C 203 5-EtO H B3 COOH CH.sub.2 J21 C 204 5-Me 6-Me B3 COOH
CH.sub.2 J21 C 205 5-Et 6-Et B3 COOH CH.sub.2 J21 C 206 5-F 6-F B3
COOH CH.sub.2 J21 C 207 5-Cl 6-Cl B3 COOH CH.sub.2 J21 C 208
5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J21 C 209 5-MeO 6-MeO B3
COOH CH.sub.2 J21 C 210 5-EtO 6-EtO B3 COOH CH.sub.2 J21 C 211 H H
B3 COOH CH.sub.2 J38 C 212 5-Me H B3 COOH CH.sub.2 J38 C 213 5-Et H
B3 COOH CH.sub.2 J38 C 214 5-F H B3 COOH CH.sub.2 J38 C 215 5-Cl H
B3 COOH CH.sub.2 J38 C 216 5-CF.sub.3 H B3 COOH CH.sub.2 J38 C 217
5-MeO H B3 COOH CH.sub.2 J38 C 218 5-EtO H B3 COOH CH.sub.2 J38 C
219 5-Me 6-Me B3 COOH CH.sub.2 J38 C 220 5-Et 6-Et B3 COOH CH.sub.2
J38 C 221 5-F 6-F B3 COOH CH.sub.2 J38 C 222 5-Cl 6-Cl B3 COOH
CH.sub.2 J38 C 223 5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J38 C 224
5-MeO 6-MeO B3 COOH CH.sub.2 J38 C 225 5-EtO 6-EtO B3 COOH CH.sub.2
J38 C 226 H H B3 COOH CH.sub.2 J42 C 227 5-Me H B3 COOH CH.sub.2
J42 C 228 5-Et H B3 COOH CH.sub.2 J42 C 229 5-F H B3 COOH CH.sub.2
J42 C 230 5-Cl H B3 COOH CH.sub.2 J42 C 231 5-CF.sub.3 H B3 COOH
CH.sub.2 J42 C 232 5-MeO H B3 COOH CH.sub.2 J42 C 233 5-EtO H B3
COOH CH.sub.2 J42 C 234 5-Me 6-Me B3 COOH CH.sub.2 J42 C 235 5-Et
6-Et B3 COOH CH.sub.2 J42 C 236 5-F 6-F B3 COOH CH.sub.2 J42 C 237
5-Cl 6-Cl B3 COOH CH.sub.2 J42 C 238 5-CF.sub.3 6-CF.sub.3 B3 COOH
CH.sub.2 J42 C 239 5-MeO 6-MeO B3 COOH CH.sub.2 J42 C 240 5-EtO
6-EtO B3 COOH CH.sub.2 J42 C 241 H H B3 COOH CH.sub.2 J44 C 242
5-Me H B3 COOH CH.sub.2 J44 C 243 5-Et H B3 COOH CH.sub.2 J44 C 244
5-F H B3 COOH CH.sub.2 J44 C 245 5-Cl H B3 COOH CH.sub.2 J44 C 246
5-CF.sub.3 H B3 COOH CH.sub.2 J44 C 247 5-MeO H B3 COOH CH.sub.2
J44 C 248 5-EtO H B3 COOH CH.sub.2 J44 C 249 5-Me 6-Me B3 COOH
CH.sub.2 J44 C 250 5-Et 6-Et B3 COOH CH.sub.2 J44 C 251 5-F 6-F B3
COOH CH.sub.2 J44 C 252 5-Cl 6-Cl B3 COOH CH.sub.2 J44 C 253
5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J44 C 254 5-MeO 6-MeO B3
COOH CH.sub.2 J44 C 255 5-EtO 6-EtO B3 COOH CH.sub.2 J44 C 256 H H
B3 COOH CH.sub.2 J63 C 257 5-Me H B3 COOH CH.sub.2 J63 C 258 5-Et H
B3 COOH CH.sub.2 J63 C 259 5-F H B3 COOH CH.sub.2 J63 C 260 5-Cl H
B3 COOH G J63 C 261 5-CF.sub.3 H B3 COOH CH.sub.2 J63 C 262 5-MeO H
B3 COOH CH.sub.2 J63 C 263 5-EtO H B3 COOH CH.sub.2 J63 C 264 5-Me
6-Me B3 COOH CH.sub.2 J63 C 265 5-Et 6-Et B3 COOH CH.sub.2 J63 C
266 5-F 6-F B3 COOH CH.sub.2 J63 C 267 5-Cl 6-Cl B3 COOH CH.sub.2
J63 C 268 5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J63 C 269 5-MeO
6-MeO B3 COOH CH.sub.2 J63 C 270 5-EtO 6-EtO B3 COOH CH.sub.2 J63 C
271 H H B9 COOH CH.sub.2 J64 C 272 5-Me H B9 COOH CH.sub.2 J64 C
273 5-Et H B9 COOH CH.sub.2 J64 C 274 5-F H B9 COOH CH.sub.2 J64 C
275 5-Cl H B9 COOH CH.sub.2 J64 C 276 5-CF.sub.3 H B9 COOH CH.sub.2
J64 C 277 5-MeO H B9 COOH CH.sub.2 J64 C 278 5-EtO H B9 COOH
CH.sub.2 J64 C 279 5-Me 6-Me B9 COOH CH.sub.2 J64 C 280 5-Et 6-Et
B9 COOH CH.sub.2 J64 C 281 5-F 6-F B9 COOH CH.sub.2 J64 C 282 5-Cl
6-Cl B9 COOH CH.sub.2 J64 C 283 5-CF.sub.3 6-CF.sub.3 B9 COOH
CH.sub.2 J64 C 284 5-MeO 6-MeO B9 COOH CH.sub.2 J64 C 285 5-EtO
6-EtO B9 COOH CH.sub.2 J64 C 286 H H B10 COOH CH.sub.2 J63 C 287
5-Me H B10 COOH CH.sub.2 J63 C 288 5-Et H B10 COOH CH.sub.2 J63 C
289 5-F H B10 COOH CH.sub.2 J63 C 290 5-Cl H B10 COOH CH.sub.2 J63
C 291 5-CF.sub.3 H B10 COOH CH.sub.2 J63 C 292 5-MeO H B10 COOH
CH.sub.2 J63 C 293 5-EtO H B10 COOH CH.sub.2 J63 C 294 5-Me 6-Me
B10 COOH CH.sub.2 J63 C 295 5-Et 6-Et B10 COOH CH.sub.2 J63 C 296
5-F 6-F B10 COOH CH.sub.2 J63 C 297 5-Cl 6-Cl B10 COOH CH.sub.2 J63
C 298 5-CF.sub.3 6-CF.sub.3 B10 COOH CH.sub.2 J63 C 299 5-MeO 6-MeO
B10 COOH CH.sub.2 J63 C 300 5-EtO 6-EtO B10 COOH CH.sub.2 J63 C 301
5-CN H B3 COOH CH.sub.2 J1 S 302 5-CN H B3 COOH CH.sub.2 J2 S 303
5-CN H B3 COOH CH.sub.2 J3 S 304 5-CN H B3 COOH CH.sub.2 J4 S 305
5-CN H B3 COOH CH.sub.2 J5 S 306 5-CN H B3 COOH CH.sub.2 J6 S 307
5-CN H B3 COOH CH.sub.2 J7 S 308 5-CN H B3 COOH CH.sub.2 J8 S 309
5-CN H B3 COOH CH.sub.2 J9 S 310 5-CN H B3 COOH CH.sub.2 J10 S 311
5-CN H B3 COOH CH.sub.2 J11 S 312 5-CN H B3 COOH CH.sub.2 J12 S 313
5-CN H B3 COOH CH.sub.2 J13 S 314 5-CN H B3 COOH CH.sub.2 J14 S 315
5-CN H B3 COOH CH.sub.2 J15 S 316 5-CN H B3 COOH CH.sub.2 J16 S 317
5-CN H B3 COOH CH.sub.2 J17 S 318 5-CN H B3 COOH CH.sub.2 J18 S 319
5-CN H B3 COOH CH.sub.2 J19 S 320 5-CN H B3 COOH CH.sub.2 J20 S 321
5-CN H B3 COOH CH.sub.2 J21 S 322 5-CN H B3 COOH CH.sub.2 J22 S 323
5-CN H B3 COOH CH.sub.2 J23 S 324 5-CN H B3 COOH CH.sub.2 J24 S 325
5-CN H B3 COOH CH.sub.2 J25 S 326 5-CN H B3 COOH CH.sub.2 J26 S 327
5-CN H B3 COOH CH.sub.2 J27 S 328 5-CN H B3 COOH CH.sub.2 J28 S 329
5-CN H B3 COOH CH.sub.2 J29 S 330 5-CN H B3 COOH CH.sub.2 J30 S 331
5-CN H B3 COOH CH.sub.2 J31 S 332 5-CN H B3 COOH CH.sub.2 J32 S 333
5-CN H B3 COOH CH.sub.2 J33 S 334 5-CN H B3 COOH CH.sub.2 J34 S 335
5-CN H B3 COOH CH.sub.2 J35 S 336 5-CN H B3 COOH CH.sub.2 J36 S 337
5-CN H B3 COOH CH.sub.2 J37 S 338 5-CN H B3 COOH CH.sub.2 J38 S 339
5-CN H B3 COOH CH.sub.2 J39 S 340 5-CN H B3 COOH CH.sub.2 J40 S 341
5-CN H B3 COOH CH.sub.2 J41 S 342 5-CN H B3 COOH CH.sub.2 J42 S 343
5-CN H B3 COOH CH.sub.2 J43 S 344 5-CN H B3 COOH CH.sub.2 J44 S 345
5-CN H B3 COOH CH.sub.2 J45 S 346 5-CN H B3 COOH CH.sub.2 J46 S 347
5-CN H B3 COOH CH.sub.2 J47 S 348 5-CN H B3 COOH CH.sub.2 J48 S 349
5-CN H B3 COOH CH.sub.2 J49 S 350 5-CN H B3 COOH CH.sub.2 J50 S 351
5-CN H B3 COOH CH.sub.2 J51 S 352 5-CN H B3 COOH CH.sub.2 J52 S 353
5-CN H B3 COOH CH.sub.2 J53 5 354 5-CN H B3 COOH CH.sub.2 J54 S 355
5-CN H B3 COOH CH.sub.2 J55 S 356 5-CN H B3 COOH CH.sub.2 J56 S 357
5-CN H B3 COOH CH.sub.2 J57 S 358 5-CN H B3 COOH CH.sub.2 J58 S 359
5-CN H B3 COOH CH.sub.2 J59 S 360 5-CN H B3 COOH CH.sub.2 J60 S 361
5-CN H B3 COOH CH.sub.2 J61 S 362 5-CN H B3 COOH CH.sub.2 J62 S 363
5-CN H B3 COOH CH.sub.2 J63 S 364 5-CN H B3 COOH CH.sub.2 J64 S 365
5-CN H B3 COOH CH.sub.2 J65 S 366 5-CN H B3 COOH CH.sub.2 J66 S 367
5-CN H B3 COOH CH.sub.2 J67 S 368 5-CN H B3 COOH CH.sub.2 J68 S 369
5-CN H B3 COOH CH.sub.2 J69 S 370 5-CN H B1 COOH CH.sub.2 J4 S 371
5-CN H B2 COOH CH.sub.2 J4 S 372 5-CN H B4 COOH CH.sub.2 J4 S 373
5-CN H B5 COOH CH.sub.2 J4 5 374 5-CN H B1 COOH CH.sub.2 J10 S 375
5-CN H B2 COOH CH.sub.2 J10 S 376 5-CN H B4 COOH CH.sub.2 J10 S 377
5-CN H B5 COOH CH.sub.2 J10 S 378 5-CN H B1 COOH CH.sub.2 J13 S 379
5-CN H B2 COOH CH.sub.2 J13 S 380 5-CN H B4 COOH CH.sub.2 J13 S 381
5-CN H B5 COOH CH.sub.2 J13 S 382 5-CN H B1 COOH CH.sub.2 J16 S 383
5-CN H B2 COOH CH.sub.2 J16 S 384 5-CN H B4 COOH CH.sub.2 J16 S 385
5-CN H B5 COOH CH.sub.2 J16 S 386 5-CN H B1 COOH CH.sub.2 J18 S 387
5-CN H B2 COOH CH.sub.2 J18 S 388 5-CN H B4 COOH CH.sub.2 J18 S 389
5-CN H B5 COOH CH.sub.2 J18 S 390 5-CN H B1 COOH CH.sub.2 J21 S 391
5-CN H B2 COOH CH.sub.2 J21 S 392 5-CN H B4 COOH CH.sub.2 J21 S 393
5-CN H B5 COOH CH.sub.2 J21 S 394 5-CN H B1 COOH CH.sub.2 J35 S 395
5-CN H B2 COOH CH.sub.2 J35 S 396 5-CN H B4 COOH CH.sub.2 J35 S 397
5-CN H B5 COOH CH.sub.2 J35 S 398 5-CN H B1 COOH CH.sub.2 J37 5 399
5-CN H B2 COOH CH.sub.2 J37 S 400 5-CN H B4 COOH CH.sub.2 J37 S 401
5-CN H B5 COOH CH.sub.2 J37 S 402 5-CN H B1 COOH CH.sub.2 J39 S 403
5-CN H B2 COOH CH.sub.2 J39 S 404 5-CN H B4 COOH CH.sub.2 J39 S 405
5-CN H B5 COOH CH.sub.2 J39 S 406 5-CN H B1 COOH CH.sub.2 J41 S 407
5-CN H B2 COOH CH.sub.2 J41 S 408 5-CN H B4 COOH CH.sub.2 J41 S 409
5-CN H B5 COOH CH.sub.2 J41 S 410 5-CN H B1 COOH CH.sub.2 J45 S 411
5-CN H B2 COOH CH.sub.2 J45 S 412 5-CN H B4 COOH CH.sub.2 J45 S 413
5-CN H B5 COOH CH.sub.2 J45 S 414 5-CN H B1 COOH CH.sub.2 J47 S 415
5-CN H B2 COOH CH.sub.2 J47 S 416 5-CN H B4 COOH CH.sub.2 J47 S 417
5-CN H B5 COOH CH.sub.2 J47 S 418 5-CN H B1 COOH CH.sub.2 J50 S 419
5-CN H B2 COOH CH.sub.2 J50 S 420 5-CN H B4 COOH CH.sub.2 J50 S 421
5-CN H B5 COOH CH.sub.2 J50 S 422 5-CN H B1 COOH CH.sub.2 J63 S 423
5-CN H B2 COOH CH.sub.2 J63 S 424 5-CN H
B4 COOH CH.sub.2 J63 S 425 5-CN H B5 COOH CH.sub.2 J63 S 426 5-CN H
B1 COOH CH.sub.2 J63 SO 427 5-CN H B2 COOH CH.sub.2 J63 SO 428 5-CN
H B3 COOH CH.sub.2 J63 SO 429 5-CN H B4 COOH CH.sub.2 J63 SO 430
5-CN H B5 COOH CH.sub.2 J63 SO 431 5-CN H B1 COOH CH.sub.2 J63
SO.sub.2 432 5-CN H B2 COOH CH.sub.2 J63 SO.sub.2 433 5-CN H B3
COOH CH.sub.2 J63 SO.sub.2 434 5-CN H B4 COOH CH.sub.2 J63 SO.sub.2
435 5-CN H B5 COOH CH.sub.2 J63 SO.sub.2 436 5-CN H B1 COOH
CH.sub.2 J63 single bond 437 5-CN H B2 COOH CH.sub.2 J63 single
bond 438 5-CN H B3 COOH CH.sub.2 J63 single bond 439 5-CN H B4 COOH
CH.sub.2 J63 single bond 440 5-CN H B5 COOH CH.sub.2 J63 single
bond 441 5-CN H B6 COOH CH.sub.2 J4 S 442 5-CN H B6 COOH CH.sub.2
J10 S 443 5-CN H B6 COOH CH.sub.2 J13 S 444 5-CN H B6 COOH CH.sub.2
J16 S 445 5-CN H B6 COOH CH.sub.2 J18 S 446 5-CN H B6 COOH CH.sub.2
J21 S 447 5-CN H B6 COOH CH.sub.2 J35 S 448 5-CN H B6 COOH CH.sub.2
J37 S 449 5-CN H B6 COOH CH.sub.2 J39 S 450 5-CN H B6 COOH CH.sub.2
J41 S 451 5-CN H B6 COOH CH.sub.2 J45 S 452 5-CN H B6 COOH CH.sub.2
J47 S 453 5-CN H B6 COOH CH.sub.2 J50 S 454 5-CN H B6 COOH CH.sub.2
J63 S 455 5-CN H B6 COOH CH.sub.2 J63 SO 456 5-CN H B6 COOH
CH.sub.2 J63 SO.sub.2 457 5-CN 457 B6 COOH CH.sub.2 J63 single bond
458 5-CN H B7 COOH CH.sub.2 J4 S 459 5-CN H B7 COOH CH.sub.2 J10 S
460 5-CN H B7 COOH CH.sub.2 J13 S 461 5-CN H B7 COOH CH.sub.2 J16 S
462 5-CN H B7 COOH CH.sub.2 J18 S 463 5-CN H B7 COOH CH.sub.2 J21 S
464 5-CN H B7 COOH CH.sub.2 J35 S 465 5-CN H B7 COOH CH.sub.2 J37 S
466 5-CN H B7 COOH CH.sub.2 J39 S 467 5-CN H B7 COOH CH.sub.2 J41 S
468 5-CN H B7 COOH CH.sub.2 J45 S 469 5-CN H B7 COOH CH.sub.2 J47 S
470 5-CN H B7 COOH CH.sub.2 J50 S 471 5-CN H B7 COOH CH.sub.2 J63 S
472 5-CN H B7 COOH CH.sub.2 J63 SO 473 5-CN H B7 COOH CH.sub.2 J63
SO.sub.2 474 5-CN H B7 COOH CH.sub.2 J63 single bond 475 5-CN H B8
COOH CH.sub.2 J10 S 476 5-CN H B8 COOH CH.sub.2 J13 S 477 5-CN H B8
COOH CH.sub.2 J13 S 478 5-CN H B8 COOH CH.sub.2 J16 S 479 5-CN H B8
COOH CH.sub.2 J18 S 480 5-CN H B8 COOH CH.sub.2 J21 S 481 5-CN H B8
COOH CH.sub.2 J35 S 482 5-CN H B8 COOH CH.sub.2 J37 S 483 5-CN H B8
COOH CH.sub.2 J39 S 484 5-CN H B8 COOH CH.sub.2 J41 S 485 5-CN H B8
COOH CH.sub.2 J45 S 486 5-CN H B8 COOH CH.sub.2 J47 S 487 5-CN H B8
COOH CH.sub.2 J50 S 488 5-CN H B8 COOH CH.sub.2 J63 S 489 5-CN H B8
COOH CH.sub.2 J63 SO 490 5-CN H B8 COOH CH.sub.2 J63 SO.sub.2 491
5-CN H B8 COOH CH.sub.2 J63 single bond 492 H H B3 COOH CH.sub.2
J64 S 493 5-Me 6-Me B3 COOH CH.sub.2 J64 S 494 H H B11 COOH
CH.sub.2 J63 S 495 5-MeO H B3 COOH CH.sub.2 J37 S 496 H H B2 COOH
CH.sub.2 J63 S 497 H H B4 COOH CH.sub.2 J63 S 498 5-Me 6-Me B3 COOH
CH.sub.2 J63 SO.sub.2 499 H H B3 COOH CH.sub.2 J3 S 500 5-Me H B3
COOH CH.sub.2 J3 S 501 5-Et H B3 COOH CH.sub.2 J3 S 502 5-F H B3
COOH CH.sub.2 J3 S 503 5-Cl H B3 COOH CH.sub.2 J3 S 504 5-CF.sub.3
H B3 COOH CH.sub.2 J3 S 505 5-MeO H B3 COOH CH.sub.2 J3 S 506 5-EtO
H B3 COOH CH.sub.2 J3 S 507 5-Me 6-Me B3 COOH CH.sub.2 J3 S 508
5-Et 6-Et B3 COOH CH.sub.2 J3 S 509 5-F 6-F B3 COOH CH.sub.2 J5 S
510 5-Cl 6-Cl B3 COOH CH.sub.2 J3 S 511 5-CF.sub.3 6-CF.sub.3 B3
COOH CH.sub.2 J3 S 512 5-MeO 6-MeO B3 COOH CH.sub.2 J3 S 513 5-EtO
6-EtO B3 COOH CH.sub.2 J3 S 514 H H B3 COOH CH.sub.2 J15 S 515 5-Me
H B3 COOH CH.sub.2 J15 S 516 5-Et H B3 COOH CH.sub.2 J15 S 517 5-F
H B3 COOH CH.sub.2 J15 S 518 5-Cl H B3 COOH CH.sub.2 J15 S 519
5-CF.sub.3 H B3 COOH CH.sub.2 J15 S 520 5-MeO H B3 COOH CH.sub.2
J15 S 521 5-EtO H B3 COOH CH.sub.2 J15 S 522 5-Me 6-Me B3 COOH
CH.sub.2 J15 S 523 5-Et 6-Et B3 COOH CH.sub.2 J15 S 524 5-F 6-F B3
COOH CH.sub.2 J15 S 525 5-Cl 6-Cl B3 COOH CH.sub.2 J15 S 526
5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J15 S 527 5-MeO 6-MeO B3
COOH CH.sub.2 J15 S 528 5-EtO 6-EtO B3 COOH CH.sub.2 J15 S 529 H H
B3 COOH CH.sub.2 J28 S 530 5-Me H B3 COOH CH.sub.2 J28 S 531 5-Et H
B3 COOH CH.sub.2 J28 S 532 5-F H B3 COOH CH.sub.2 J28 S 533 5-Cl H
B3 COOH CH.sub.2 J28 S 534 5-CF.sub.3 H B3 COOH CH.sub.2 J28 S 535
5-MeO H B3 COOH CH.sub.2 J28 S 536 5-EtO H B3 COOH CH.sub.2 J28 S
537 5-Me 6-Me B3 COOH CH.sub.2 J28 S 538 5-Et 6-Et B3 COOH CH.sub.2
J28 S 539 5-F 6-F B3 COOH CH.sub.2 J28 S 540 5-Cl 6-Cl B3 COOH
CH.sub.2 J28 S 541 5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J28 S 542
5-MeO 6-MeO B3 COOH CH.sub.2 J28 S 543 5-EtO 6-EtO B3 COOH CH.sub.2
J28 S 544 H H B3 COOH CH.sub.2 J35 S 545 5-Me H B3 COOH CH.sub.2
J35 S 546 5-Et H B3 COOH CH.sub.2 J35 S 547 5-F H B3 COOH CH.sub.2
J35 S 548 5-Cl H B3 COOH CH.sub.2 J35 S 549 5-CF.sub.3 H B3 COOH
CH.sub.2 J35 S 550 5-MeO H B3 COOH CH.sub.2 J35 S 551 5-EtO H B3
COOH CH.sub.2 J35 S 552 5-Me 6-Me B3 COOH CH.sub.2 J35 S 553 5-Et
6-Et B3 COOH CH.sub.2 J35 S 554 5-F 6-F B3 COOH CH.sub.2 J35 S 555
5-Cl 6-Cl B3 COOH CH.sub.2 J35 S 556 5-CF.sub.3 6-CF.sub.3 B3 COOH
CH.sub.2 J35 S 557 5-MeO 6-MeO B3 COOH CH.sub.2 J35 S 558 5-EtO
6-EtO B3 COOH CH.sub.2 J35 S 559 H H B3 COOH CH.sub.2 J37 S 560
5-Me H B3 COOH CH.sub.2 J37 S 561 5-Et H B3 COOH CH.sub.2 J37 S 562
5-F H B3 COOH CH.sub.2 J37 S 563 5-Cl H B3 COOH CH.sub.2 J37 S 564
5-CF.sub.3 H B3 COOH CH.sub.2 J37 S 565 5-MeO H B3 COOH CH.sub.2
J37 S 566 5-EtO H B3 COOH CH.sub.2 J37 S 567 5-Me 6-Me B3 COOH
CH.sub.2 J37 S 568 5-Et 6-Et B3 COOH CH.sub.2 J37 S 569 5-F 6-F B3
COOH CH.sub.2 J37 S 570 5-Cl 6-Cl B3 COOH CH.sub.2 J37 S 571
5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J37 S 572 5-MeO 6-MeO B3
COOH CH.sub.2 J37 S 573 5-EtO 6-EtO B3 COOH CH.sub.2 J37 S 574 H H
B3 COOH CH.sub.2 J39 S 575 5-Me H B3 COOH CH.sub.2 J39 S 576 5-Et H
B3 COOH CH.sub.2 J39 S 577 5-F H B3 COOH CH.sub.2 J39 S 578 5-Cl H
B3 COOH CH.sub.2 J39 S 579 5-CF.sub.3 H B3 COOH CH.sub.2 J39 S 580
5-MeO H B3 COOH CH.sub.2 J39 S 581 5-EtO H B3 COOH CH.sub.2 J39 S
582 5-Me 6-Me B3 COOH CH.sub.2 J39 S 583 5-Et 6-Et B3 COOH CH.sub.2
J39 S 584 5-F 6-F B3 COOH CH.sub.2 J39 S 585 5-Cl 6-Cl B3 COOH
CH.sub.2 J39 S 586 5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J39 S 587
5-MeO 6-MeO B3 COOH CH.sub.2 J39 S 588 5-EtO 6-EtO B3 COOH CH.sub.2
J39 S 589 H H B3 COOH CH.sub.2 J41 S 590 5-Me H B3 COOH CH.sub.2
J41 S 591 5-Et H B3 COOH CH.sub.2 J41 S 592 5-F H B3 COOH CH.sub.2
J41 S 593 5-Cl H B3 COOH CH.sub.2 J41 S 594 5-CF.sub.3 H B3 COOH
CH.sub.2 J41 S 595 5-MeO H B3 COOH CH.sub.2 J41 S 596 5-EtO H B3
COOH CH.sub.2 J41 S 597 5-Me 6-Me B3 COOH CH.sub.2 J41 S 598 5-Et
6-Et B3 COOH CH.sub.2 J41 S 599 5-F 6-F B3 COOH CH.sub.2 J41 S 600
5-Cl 6-Cl B3 COOH CH.sub.2 J41 S 601 5-CF.sub.3 6-CF.sub.3 B3 COOH
CH.sub.2 J41 S 602 5-MeO 6-MeO B3 COOH CH.sub.2 J41 S 603 5-EtO
6-EtO B3 COOH CH.sub.2 J41 S 604 H H B3 COOH CH.sub.2 J45 S 605
5-Me H B3 COOH CH.sub.2 J45 S 606 5-Et H B3 COOH CH.sub.2 J45 S 607
5-F H B3 COOH CH.sub.2 J45 S 608 5-Cl H B3 COOH CH.sub.2 J45 S 609
5-CF.sub.3 H B3 COOH CH.sub.2 J45 S 610 5-MeO H B3 COOH CH.sub.2
J45 S 611 5-EtO H B3 COOH CH.sub.2 J45 S 612 5-Me 6-Me B3 COOH
CH.sub.2 J45 S 613 5-Et 6-Et B3 COOH CH.sub.2 J45 S 614 5-F 6-F B3
COOH CH.sub.2 J45 S 615 5-Cl 6-Cl B3 COOH CH.sub.2 J45 S 616
5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J45 5 617 5-MeO 6-MeO B3
COOH CH.sub.2 J45 S 618 5-EtO 6-EtO B3 COOH CH.sub.2 J45 S 619 H H
B3 COOH CH.sub.2 J47 S 620 5-Me H B3 COOH CH.sub.2 J47 S 621 5-Et H
B3 COOH CH.sub.2 J47 S 622 5-F H B3 COOH CH.sub.2 J47 S 623 5-Cl H
B3 COOH CH.sub.2 J47 S 624 5-CF.sub.3 H B3 COOH CH.sub.2 J47 S 625
5-MeO H B3 COOH CH.sub.2 J47 S 626 5-EtO H B3 COOH CH.sub.2 J47 S
627 5-Me 6-Me B3 COOH CH.sub.2 J47 S 628 5-Et 6-Et B3 COOH CH.sub.2
J47 S 629 5-F 6-F B3 COOH CH.sub.2 J47 S 630 5-Cl 6-Cl B3 COOH
CH.sub.2 J47 S 631 5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J47 S 632
5-MeO 6-MeO B3 COOH CH.sub.2 J47 S 633 5-EtO 6-EtO B3 COOH CH.sub.2
J47 S 634 5-EtO H B3 COOH CH.sub.2 J47 S 635 5-Me 6-Me B3 COOH
CH.sub.2 J47 S 636 5-Et 6-Et B3 COOH CH.sub.2 J47 S 637 5-F 6-F B3
COOH CH.sub.2 J47 S 638 5-Cl 6-Cl B3 COOH CH.sub.2 J47 S 639
5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J47 S 640 5-MeO 6-MeO B3
COOH CH.sub.2 J47 S 641 5-EtO 6-EtO B3 COOH CH.sub.2 J47 S 642 H H
B3 COOH CH.sub.2 J50 S 643 5-Me H B3 COOH CH.sub.2 J50 S 644 5-Et H
B3 COOH CH.sub.2 J50 S 645 5-F H B3 COOH CH.sub.2 J50 S 646 5-Cl H
B3 COOH CH.sub.2 J50 S 647 5-CF.sub.3 H B3 COOH CH.sub.2 J50 S 648
5-MeO H B3 COOH CH.sub.2 J50 S 649 5-EtO H B3 COOH CH.sub.2 J50 S
650 5-Me 6-Me B3 COOH CH.sub.2 J50 S 651 5-Et 6-Et B3 COOH CH.sub.2
J50 S 652 5-F 6-F B3 COOH CH.sub.2 J50 S 653 5-Cl 6-Cl B3 COOH
CH.sub.2 J50 S 654 5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J50 S 655
5-MeO 6-MeO B3 COOH CH.sub.2 J50 S 656 5-EtO 6-EtO B3 COOH CH.sub.2
J50 S 657 5-Me H B3 COOH CH.sub.2 J54 S 658 5-Et H B3 COOH CH.sub.2
J54 S 659 5-F H B3 COOH CH.sub.2 J54 S 660 5-Cl H B3 COOH CH.sub.2
J54 S 661 5-CF.sub.3 H B3 COOH CH.sub.2 J54 S 662 5-MeO H B3 COOH
CH.sub.2 J54 S 663 5-EtO H B3 COOH CH.sub.2 J54 S 664 5-Me 6-Me B3
COOH CH.sub.2 J54 S 665 5-Et 6-Et B3 COOH CH.sub.2 J54 S 666 5-F
6-F B3 COOH CH.sub.2 J54 S 667 5-Cl 6-Cl B3 COOH CH.sub.2 J54 S 668
5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J54 S 669 5-MeO 6-MeO B3
COOH CH.sub.2 J54 S 670 5-EtO 6-EtO B3 COOH CH.sub.2 J54 S 671 H H
B3 COOH CH.sub.2 J62 S 672 5-Me H B3 COOH CH.sub.2 J62 S 673 5-Et H
B3 COOH CH.sub.2 J62 S 674 5-F H B3 COOH CH.sub.2 J62 S 675 5-Cl H
B3 COOH CH.sub.2 J62 S 676 5-CF.sub.3 H B3 COOH CH.sub.2 J62 S 677
5-MeO H B3 COOH CH.sub.2 J62 S 678 5-EtO H B3 COOH CH.sub.2 J62 S
679 5-Me 6-Me B3 COOH CH.sub.2 J62 S 680 5-Et 6-Et B3 COOH CH.sub.2
J62 S 681 5-F 6-F B3 COOH CH.sub.2 J62 S 682 5-Cl 6-Cl B3 COOH
CH.sub.2 J62 S 683 5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J62 S 684
5-MeO 6-MeO B3 COOH CH.sub.2 J62 S 685 5-EtO 6-EtO B3 COOH CH.sub.2
J62 S 686 5-Me H B3 COOH CH.sub.2 J64 S 687 5-Et H B3 COOH CH.sub.2
J64 S 688 5-F H B3 COOH CH.sub.2 J64 S 689 5-Cl H B3 COOH CH.sub.2
J64 S 690 5-CF.sub.3 H B3 COOH CH.sub.2 J64 S 691 5-MeO H B3 COOH
CH.sub.2 J64 S 692 5-EtO H B3 COOH CH.sub.2 J64 S 693 5-Et 6-Et B3
COOH CH.sub.2 J64 S 694 5-F 6-F B3 COOH CH.sub.2 J64 S 695 5-Cl
6-Cl B3 COOH CH.sub.2 J64 S 696 5-CF.sub.3 6-CF.sub.3 B3 COOH
CH.sub.2 J64 S 697 5-MeO 6-MeO B3 COOH CH.sub.2 J64 S 698 5-EtO
6-EtO B3 COOH CH.sub.2 J64 S 699 H H B3 COOH CH.sub.2 J65 S 700
5-Me H B3 COOH CH.sub.2 J65 S 701 5-Et H B3 COOH CH.sub.2 J65 S 702
5-F H B3 COOH CH.sub.2 J65 S 703 5-Cl H B3 COOH CH.sub.2 J65 S 704
5-CF.sub.3 H B3 COOH CH.sub.2 J65 S 705 5-MeO H B3 COOH CH.sub.2
J65 S 706 5-EtO H B3 COOH CH.sub.2 J65 S 707 5-Me 6-Me B3 COOH
CH.sub.2 J65 S 708 5-Et 6-Et B3 COOH CH.sub.2 J65 S 709 5-F 6-F B3
COOH CH.sub.2 J65 S 710 5-Cl 6-Cl B3 COOH CH.sub.2 J65 S 711
5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J65 S 712 5-MeO 6-MeO B3
COOH CH.sub.2 J65 S 713 5-EtO 6-EtO B3 COOH CH.sub.2 J65 S 714 H H
B3 COOH CH.sub.2 J66 S 715 5-Me H B3 COOH CH.sub.2 J66 S 716 5-Et H
B3 COOH CH.sub.2 J66 S 717 5-F H B3 COOH CH.sub.2 J66 S 718 5-Cl H
B3 COOH CH.sub.2 J66 S 719 5-CF.sub.3 H B3 COOH CH.sub.2 J66 S 720
5-MeO H B3 COOH CH.sub.2 J66 S 721 5-EtO H B3 COOH CH.sub.2 J66 S
722 5-Me 6-Me B3 COOH CH.sub.2 J66 S 723 5-Et 6-Et B3 COOH CH.sub.2
J66 S 724 5-F 6-F B3 COOH CH.sub.2 J66 S 725 5-Cl 6-Cl B3 COOH
CH.sub.2 J66 S 726 5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J66 S 727
5-MeO 6-MeO B3 COOH CH.sub.2 J66 S 728 5-EtO 6-EtO B3 COOH CH.sub.2
J66 S 729 H H B3 COOH CH.sub.2 J72 S 730 5-Me H B3 COOH CH.sub.2
J72 S 731 5-Et H B3 COOH CH.sub.2 J72 S 732 5-F H B3 COOH CH.sub.2
J72 S 733 5-Cl H B3 COOH CH.sub.2 J72 S 734 5-CF.sub.3 H B3 COOH
CH.sub.2 J72 S 735 5-MeO H B3 COOH CH.sub.2 J72 S 736 5-EtO H B3
COOH CH.sub.2 J72 S 737 5-Me 6-Me B3 COOH CH.sub.2 J72 S 738 5-Et
6-Et B3 COOH CH.sub.2 J72 S 739 5-F 6-F B3 COOH CH.sub.2 J72 S 740
5-Cl 6-Cl B3 COOH CH.sub.2 J72 S 741 5-CF.sub.3 6-CF.sub.3 B3 COOH
CH.sub.2 J72 S 742 5-MeO 6-MeO B3 COOH CH.sub.2 J72 S 743 5-EtO
6-EtO B3 COOH CH.sub.2 J72 S 744 H H B3 COOH CH.sub.2 J73 S 745
5-Me H B3 COOH CH.sub.2 J73 S 746 5-Et H B3 COOH CH.sub.2 J73 S 747
5-F H B3 COOH CH.sub.2 J73 S 748 5-Cl H B3 COOH CH.sub.2 J73 S 749
5-CF.sub.3 H B3 COOH CH.sub.2 J73 S 750 5-MeO H B3 COOH CH.sub.2
J73 S 751 5-EtO H B3 COOH CH.sub.2 J73 S 752 5-Me 6-Me B3 COOH
CH.sub.2 J73 S 753 5-Et 6-Et B3 COOH CH.sub.2 J73 S 754 5-F 6-F B3
COOH CH.sub.2 J73 S 755 5-Cl 6-Cl B3 COOH CH.sub.2 J73 S 756
5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J73 S 757 5-MeO 6-MeO B3
COOH CH.sub.2 J73 S 758 5-EtO 6-EtO B3 COOH CH.sub.2 J73 S 759 H H
B3 COOH CH.sub.2 J74 S 760 5-Me H B3 COOH CH.sub.2 J74 S 761 5-Et H
B3 COOH CH.sub.2 J74 S 762 5-F H B3 COOH CH.sub.2 J74 S 763 5-Cl H
B3 COOH CH.sub.2 J74 S 764 5-CF.sub.3 H B3 COOH CH.sub.2 J74 S 765
5-MeO H B3 COOH CH.sub.2 J74 S 766 5-EtO H B3 COOH CH.sub.2 J74 S
767 5-Me 6-Me B3 COOH CH.sub.2 J74 S 768 5-Et 6-Et B3 COOH CH.sub.2
J74 S 769 5-F 6-F B3 COOH CH.sub.2 J74 S 770 5-Cl 6-Cl B3 COOH
CH.sub.2 J74 S 771 5-CF.sub.3 6-CF.sub.3 B3 COOH CH.sub.2 J74 S 772
5-MeO 6-MeO B3 COOH CH.sub.2 J74 S 772 5-EtO 6-EtO B3 COOH CH.sub.2
J74 S
[0052] In benzimidazole derivatives (1) used in the present
invention (in some case, this is described as "of the present
invention"), in the case where E is COOH and M is S, a derivative
can be manufactured, for example, by the following synthetic
process (A).
[0053] Synthetic Process (A) 7
[0054] [in the formula, Z is halogen, and the ring marked with A,
and B, X.sup.1, X.sup.2, R.sup.4, G and J are defined in the same
manner as mentioned above].
[0055] Here, the case where the ring marked with A is a benzene
ring is explained; however, the processes can be considered to be
same also in the case where it is a pyridine ring.
[0056] That is, the amino group of a 2-nitroaniline derivative (a1)
is protected with L to give (a2). This compound is made to react
with a halide derivative (a3) to give (a4), and this compound is
deprotected to give (a5). The nitro group of (a5) is subjected to a
reductive reaction to give an orthophenylenediamine derivative
(a6). The derivative is treated with CS.sub.2 or potassium
ethylxanthate to yield a compound (a7), and subsequently this
compound is made to react with a halide ester derivative (a8) to
afford a compound (a9) of the present invention. If necessary, the
--COOR.sup.4 of the compound (a9) is hydrolyzed, so that one can
obtain a benzimidazole derivative (a10) of the present invention in
which R.sup.4 is a hydrogen atom. In addition, it is possible
directly to obtain the compound (a5) by reacting the halide
derivative (a3) with the 2-nitroaniline derivative (a1) as it is
not protected. Examples of the protecting group L include a
trifluoroacetyl group, an acetyl group, a t-butoxycarbonyl group, a
benzyl group and the like.
[0057] The reaction of a 2-nitroaniline derivative (a2) with a
halide derivative (a3) can be carried out according to the reaction
conditions of a common N-alkylation or N-acylation, for example, in
the presence of NaH, Et.sub.3N, NaOH, K.sub.2CO.sub.3 or the like
by stirring at an appropriate temperature from 0.degree. C. to
200.degree. C.
[0058] The reductive reaction of the nitro group can be carried out
according to the common reaction conditions of catalytic reduction,
for example, by allowing the nitro group to react with hydrogen gas
in the presence of a catalyst such as Pd-C or the like at a
temperature from room temperature to 100.degree. C. under an
acidic, neutral or basic condition. In addition, the reaction can
be carried out according to a method in which the nitro group is
treated with zinc or tin under an acidic condition, or a method in
which the nitro group is treated with zinc powder under a neutral
or basic condition.
[0059] The cyclization of the orthophenylenediamine derivative (a6)
can be carried out by using CS.sub.2 or potassium ethylxanthate.
The reaction using CS.sub.2 can be performed, for example,
according to the method (in a pyridine solution) described in J.
Org. Chem., 631-637, Vol. 19 (1954) or the method (in an ethanol
solution) described in J. Med. Chem., 1175-1187, Vol. 36 (1993).
The reaction using potassium ethylxanthate can be performed
according to the method described in Organic Synthesis, 569-570,
Vol. 4 (1963).
[0060] The reaction of a thiobenzimidazole (a7) with a halide ester
(a8) can be carried out according to conditions of a common
S-alkylation reaction, for example, in the presence of a base such
as NaH, Et.sub.3N, NaOH, K.sub.2CO.sub.3 or the like by stirring at
a temperature from 0.degree. C. to 200.degree. C.
[0061] The elimination reaction of a carboxy protection group
R.sup.4 is preferably carried out by using a method in which
hydrolysis is performed with an alkali such as lithium hydroxide or
an acid such as hydrochloric acid or trifluoroacetic acid.
[0062] There is no special limitation on the synthesis of the
above-mentioned halide derivative; however, the halide derivative
can be synthesized, for example, according to halogenation of a
hydroxyl group, a radical halogenation reaction of a methyl group
or the like which is generally used in organic syntheses.
[0063] In benzimidazole derivatives (1) of the present invention,
in the case where E is COOH, M is S, and G is an amide bond, a
derivative can be manufactured by the following synthetic process
(B).
[0064] Synthetic Process (B) 8
[0065] [in the formula, Q is a methylene group, a phenylene group
or the like; Z is a halogen atom; the ring marked with A, and
X.sup.1, X.sup.2, J and L are defined in the same manner as
mentioned above].
[0066] Here, the processes are explained in the case where the ring
marked with A is a benzene ring; however, the processes may be
considered to be same also in the case where it is a pyridine
ring.
[0067] That is, an aniline derivative (a2) is made to react with a
tert-butyl ester halide (b1) to give a compound (b2), and this
compound is hydrolyzed under an acidic condition to give (b3). The
obtained product (b3) is allowed to condense with an amine
derivative (b4) to give (b5). Subsequently, the reductive reaction,
the cyclization, the alkylation and the deprotection are carried
out in the same manner as in the synthetic process (A), and a
benzumidazole derivative of the present invention can be
obtained.
[0068] The condensation amidation is carried out under the
conditions of a common process using a condensing agent. Examples
of the condensing agent are DCC, DIPC, EDC.dbd.WSCI, WSCI.HCl, BOP,
DPPA and the like. The condensing agent is used singly or in
combination with HONSu, HOBt, HOOBt or the like. The reaction is
carried out in an appropriate solvent such as THF, chloroform,
t-butanol or the like at an appropriate temperature from 0.degree.
C. to 200.degree. C.
[0069] In thiobenzimidazole derivatives (1) of the present
invention, in the case where E is COOH, M is S, and G is an ether
bond, a derivative can be manufactured by the following synthetic
process (C).
[0070] Synthetic Process (C) 9
[0071] [in the formula, Z is halogen; the ring marked with A, and
X.sup.1, X.sup.2, J and L are defined in the same manner as
mentioned above].
[0072] Here, the processes are explained in the case where the ring
marked with A is a benzene ring; however, the processes may be
considered to be same also in the case where it is a pyridine
ring.
[0073] That is, an aniline derivative (a2) is made to react, for
example, with a haloalcohol derivative (c1) to give a compound
(c2). The compound (c2) is allowed to react with a phenol
derivative (c3) to give an ethereal body (c4), and the compound
(c4) is hydrolyzed to give (c5). Subsequently, the reductive
reaction, the cyclization, the alkylation and the deprotection are
carried out in the same manner as in the synthetic process (A), and
a benzimidazole derivative of the present invention can be
obtained.
[0074] The etherification is carried out by using a phosphine
compound such as LS triphenylphosphine or tributylphosphine, and an
azo compound such as DEAD or TMAD in an appropriate solvent such as
N-methylmorpholine or THF at an appropriate temperature from
0.degree. C. to 200.degree. C. by Mitsunobu Reaction or its
analogous reaction. Other reactions can be carried out in the same
manners as in the synthetic process (A).
[0075] In benzimidazole derivatives (1) of the present invention,
in the case where M is sulfoxide or sulfone, a derivative can be
manufactured by the following synthetic process (D).
[0076] Synthetic Process (D) 10
[0077] [in the formula, the ring marked with A, and B, X.sup.1,
X.sup.2, J and R.sup.4 are defined in the same manner as mentioned
above].
[0078] That is, a thiobenzimidazole compound (a9) is made to react
with a peroxide compound in an appropriate solvent to give a
suloxide derivative (d1) and/or a sulfone derivative (d2). The
peroxide compound to be used is, for example, perbenzoic acid,
m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide or the
like; and the solvent to be used is, for example, chloroform,
dichloromethane or the like. The using ratio of the compound (a9)
to the peroxide compound is not specifically limited, and it can be
appropriately selected from a wide range; however, generally
speaking, they are used preferably at about 1.2 to 5 times molar
ratio. Each reaction is carried out commonly at a temperature from
0.degree. C. to 50.degree. C., preferably from 0.degree. C. to room
temperature, and the reaction finishes generally at about 4 to 20
hr.
[0079] In benzimidazole derivatives (1) of the present invention,
in the case where M is a single bond, a derivative can be
manufactured by the following synthetic process (E).
[0080] Synthetic Process (E) 11
[0081] [in the formula, the ring marked with A, and B, X.sup.1,
X.sup.2, G, J and R.sup.4 are defined in the same manner as
mentioned above].
[0082] That is, a benzimidazole derivative (e2) can be obtained by
reacting an orthophenylenediamine derivative (a6) with a known acid
chloride derivative (e1). A bennimidazole derivative (e3) of the
present invention can be obtained by hydrolyzing the --COOR.sup.4
moiety of the compound (e2) at need.
[0083] In addition, a benzimidazole derivative of the present
invention can be synthesized referring to the method of J. Med.
Chem., 1175-1187, Vol. 36 (1993), U.S. Pat. No. 5,124,336, U.S.
Pat. No. 5,021,443 or the like.
[0084] At need, a benzimidazole derivative of the present invention
can be converted to a pharmaceutically permissible nontoxic
cationic salt. The salt is formed with an alkali metal ion such as
Na.sup.+ or K.sup.+; an alkaline earth metal ion such as Mg.sup.+
or Ca.sup.+; a metal ion such as Al.sup.3+ or Zn.sup.2+; or an
organic base such as ammonia, triethylamine, ethylenediamine,
propanediamine, pyrrolidine, piperidine, piperazine, pyridine,
lysine, choline, ethanolamine, N,N-dimethylethanolamine,
4-hydroxypiperidine, glucosamine or N-methylglucamine. Na.sup.+,
Ca.sup.2+, lysine, choline, N,N-dimethylethanolamine and
N-methylglucamine are especially preferable.
[0085] A benzimidazole derivative expressed by the above formula
(1) of the present invention has an activity for inhibiting human
chymase activity, and can be used as a preventive agent and/or a
treating agent which is clinically applicable as human chymase
inhibitor.
[0086] In addition, a benzimidazole derivative of the present
invention can be administered orally or parentally by preparing a
pharmaceutical composition with a pharmaceutically permissible
carrier and formulating the composition into various dosage forms.
The parenteral administrations are, for example, intravenous,
subcutaneous, intramuscular, percutaneous, intrarectal and nasal
administrations, and instillation.
[0087] The dosage forms of the pharmaceutical composition are the
following. In the case of an oral administration agent, they are
tables, pills, granules, powder, a solution, a suspension, a syrup,
capsules and the like.
[0088] Here, the tables can be formulated according to a common
method by using pharmaceutically permissible carriers such as a
filler, a binder and a disintegrator. The pills, granules and
powder also can be formulated according to common methods by using
a filler and the like in the same manner as in the tablets. The
solution, suspension and syrup can be formulated according to
common methods by using a glycerin ester, an alcohol, water, a
vegetable oil or the like. The capsules can be formulated by fining
granules, powder, a solution or the like in a gelatin capsule or
the like.
[0089] Out of the parenteral administrations, in the cases of the
intravenous administration, subcutaneous administration and
intramuscular administration, the agent can be administered in a
dosage form of an injection. The injection is prepared by
dissolving a benzimidazole derivative, for example, in a
water-soluble solvent such as physiological saline or by dissolving
a benzimidazole derivative, for example, in a water-insoluble
solvent consisting of propylene glycol, polyethylene glycol or an
organic ester such as a vegetable oil.
[0090] In the case of the percutaneous administration, the agent
can be used in a dosage form, for example, of an ointment, a cream
or the like. The ointment can be formulated by mixing a
benzimidazole derivative with a fat and oil, vaseline or the like.
The cream can be formulated by mixing a benzimidazole derivative
with an emulsifier.
[0091] In the case of the intrarectal administration, the agent can
be formulated into a suppository by using a gelatin soft capsule or
the like.
[0092] In the case of the nasal administration, the agent can be
used in a dosage form consisting of a liquid or powdery
composition. As the base of the liquid agent, water, saline, a
phosphate buffer, an acetate buffer or the like is used, and the
base may further contain a surfactant, an antioxidant, a
stabilizer, a preservative or a thickener. The bases of the powdery
agent are, for example, a water-absorbing substance such as an
easily water-soluble polyacrylic acid salt, a cellulose lower alkyl
ether, polyethylene glycol, polyvinyl pyrrolidone, amylose or
pullulan, and, for example, a scarcely watersoluble substance such
as a cellulose, a starch, a protein, a gum or a cross-linked vinyl
polymer. The water-absorbing substance is preferred as the base.
Further, these substances may be used by mixing with each other.
Furthermore, to the powdery dosage form, an antioxidant, a coloring
agent, a preservative, an antiseptic, a corrigent or the like may
be added. Each of the liquid agent and powdery agent can be
administered, for example, by using a sprayer or the like.
[0093] In the case of instillation, the agent can be used in the
form of an aqueous or nonaqueous eye drop. In the aqueous eye drop,
as the solvent, sterile purified water, physiological saline or the
like can be used. In the case where only the sterile purified water
is used as the solvent, the agent can be used in an aqueous
suspension eye drop by adding a suspending agent such as a
surfactant or a polymeric thickener, and in addition, it can be
used in the form of a solubilized, eye drop by adding a solubilizer
such as a nonionic surfactant.
[0094] In the nonaqueous eye drop, a nonaqueous solvent for
injection can be used as the solvent, and the formed eye drop can
be used as a nonaqueous suspension eye drop.
[0095] In the case where the agent is administered into an eye by a
method other than the eye drops, it is formulated into an
ophthalmic ointment, a coating solution, a catapasm, an insert or
the like.
[0096] Further, in the case where the agent is inhaled through the
noses, the mouth or the like, it is inhaled in a dosage form of a
solution or a suspension consisting of a benzimidazole derivative
and a generally used pharmaceutical vehicle by using, for example,
an aerosol sprayer for inhalation or the like. Further, a
benzimidazole derivative formed into a dry powdery body can be
administered by using an inhalator or the like which allows the
powdery body to come into direct contact with the lung.
[0097] Into these various pharmaceutical preparations, a
pharmaceutically permissible support such as an isotonizing agent,
a preservative, an antiseptic, a wetting agent, a buffering agent,
an emulsifier, a dispersing agent or a stabilizer can be added at
need.
[0098] In addition, these various pharmaceutical preparations can
be sterilized through a treatment such as the addition of a
sterilizing agent, the filtration using a bacteria retention
filter, heating or irradiation at need. Or, an aseptic solid
preparation is produced, and the preparation is dissolved or
suspended in an appropriate aseptic solution directly before the
use.
[0099] The dose of the benzimidazole derivative of the present
invention depends on the kind of the disease, the administration
route, the symptom, the age, the sex and the body weight of the
patient, and the like; however, in oral administration, it is
generally about 1-500 mg/day/person, preferably, 10-300
mg/day/person. In the case of a parenteral administration such as
intravenous, subcutaneous, intramuscular, percutaneous, intrarectal
or nasal administration, instillation, or inhalation, it is about
0.1-100 mg/day/person, preferably 0.3-30 mg/day/person.
[0100] Here, examples of the disease associated with human chymase
include inflammatory diseases, allergy diseases, respiratory
diseases, cardiovascular diseases, bone/cartridge metabolic
diseases and the like.
[0101] Further, when an inhibitor against human chymase activity of
the present invention is used as a preventing agent, it can be
administered according to a known method in advance in accordance
with each symptom.
EXAMPLES
[0102] The present invention will be explained henceforth with
examples, while the present invention is not restricted by the
examples.
Example 1
[0103] Production of
4-((1-((1-naphthyl)methyl)-5-methoxybenzimidazole)-2--
ylthio)butyric Acid (Compound No. 127)
[0104] [Process 1]
[0105] 3,026 mg of 4-methoxy-2-nitroaniline (18 mmol) was dissolved
in 60 ml of acetonitrile, and the resulting solution was refluxed
for 3 hr after the addition of 3.00 ml of trifluoroacetic anhydride
(21.6 mmol). After it was cooled to room temperature, the reaction
mixture was concentrated in vacuo, and the residue was crystallized
with adding hexane. This was filtered, and the product on the
filter was dried to give 1.396 g of
4-methoxy-2-nitrotrifluoroacetanilide (82% yield).
[0106] [Process 2]
[0107] Subsequently, 1.59 g of
4-methoxy-2-nitrotrifluoroacetanilide (6 mmol) was dissolved in 20
ml of N,N-dimethylformamide, to the solution were added 1.27 g of
potassium carbonate (7.2 mmol) and 1.08 g of
1-chloromethylnaphthalene (7.8 mmol), and the mixture was stirred
at 100.degree. C. for 3 hr. After 3 hr, into the reaction mixture
was added 10 ml of 5M sodium hydroxide aqueous solution, and the
resulting mixture was heated at 100.degree. C. for 1.5 hr. The
reaction mixture was cooled to room temperature, and dissolved in
100 ml of diethyl ether, and the solution was washed with 50 ml of
water and dried over magnesium sulfate. The organic layer was
concentrated in vacuo, the residue was purified by silica gel
column chromatography (hexane:ethyl acetate=5:1), the objective
fraction was concentrated in vacuo, and the residue was dried to
yield 1.476 g of orange colored solid of ((1-naphthyl)methyl)
(4-methoxy-2-nitrophenyl)amine (80% yield).
[0108] [Process 3]
[0109] Subsequently, to 1.476 g of
((1-naphthyl)methyl)(4-methoxy-2-nitrop- henyl)amine (4.79 mmol)
were added 8 ml of 1,4-dioxane and 8 ml of ethanol, and further 0.6
ml of SM aqueous solution of sodium hydroxide and 1.25 g of zinc
powder, and the resulting mixture was heated at 100. After 2 hr
heating, 0.6 ml of 5M aqueous solution of sodium hydroxide and 1.25
g of zinc powder were further added to the reaction mixture, and
heating was continued. After 3 hr from the start of the reaction,
the reaction mixture was cooled to room temperature, it was
filtered through celite, and the filtrate was concentrated in
vacuo. The obtained residue was dissolved in ethyl acetate, and the
solution was washed with brine and concentrated in vacuo. The
residue was dried to give 1.21 g of brown oily
((1-naphthyl)methyl)(2-amino-4-methoxyphenyl)amine (91% yield).
[0110] [Process 4]
[0111] Successively, 1.2 g of
((1-naphthyl)methyl)(2-amino-4-methoxyphenyl- )amine (4.3 mmol) was
dissolved in 30 ml of ethanol, and the solution was refluxed after
the addition of 10 ml of carbon disulfide. After 12 hr, the
reaction mixture was concentrated in vacuo, 10 ml of ethanol was
added to the residue, and the mixture was treated in an ultrasonic
bath. The formed solid was filtered, and it was washed with ethanol
(2 ml.times.2) and dried to yield 620 mg of
1-(1-naphthyl)methyl-5-methoxybe- nzimidazole-2-thiol (45% yield in
two processes).
[0112] [Process 5]
[0113] To 32 mg of
1-(1-naphthyl)methyl-5-methoxybenzimidazole-2-thiol (0.1 mmol) was
added 2 ml of N,N-dimethylformamide, and subsequently 21 .mu.l of
triethylamine (0.15 mmol) and then 17 .mu.l of ethyl
4-bromo-n-butyrate (0.12 mmol) were added. The mixture was stirred
at 80.degree. C. for 10 hr under heating. Subsequently, water was
added to the reaction mixture, the resulting mixture was extracted
with diethyl ether, and the organic layer was concentrated in
vacuo. The residue was purified by preparative thin layer
chromatography (hexane:ethyl acetate=1:1), and the product was
collected and dried.
[0114] [Process 6]
[0115] Successively, the obtained residue was dissolved in 5 ml of
methanol, 0.5 ml of 4M aqueous solution of lithium hydroxide was
added to the solution, and the mixture was heated at 50.degree. C.
for 3 hr. After 3 hr, the reaction mixture was neutralized with 6M
hydrochloric acid, and the mixture was extracted with chloroform.
The organic layer was concentrated in vacuo, and the residue was
purified by a preparative thin layer chromatography (hexane-ethyl
acetate=1:1). The objective fraction was concentrated, and the
residue was dried to yield 13.4 mg of
4-((1-((1-naphthyl)methyl)-5-methoxybenzimidazole)-2-ylthio)butyric
acid (33% yield in two processes).
[0116] LC-MS:calculated value=406.14, and measured value
(M+1).sup.+=407.3
Example 2
[0117] Production of
4-((1-naphthyl)methyl)-5,6-difluorobenzimidazole)-2-y-
lthio)butyric Acid (Compound No. 131)
[0118] 500 mg of 3,4-difluoro-5-nitroaniline (2.87 mmol) was
dissolved in 5 ml of ethanol, to the solution was added 50 mg of
10% palladium-carbon, and the mixture was heated at 50.degree. C.
for 12 hr after the atmosphere was substituted with hydrogen. The
reaction mixture was cooled and filtered through celite. The
filtrate was concentrated in vacuo, and the residue was dried to
give 409 mg of 2-amino-4,5-difluoroaniline.
[0119] Successively, to the obtained 2-amino-4,5-difluoroaniline as
it is were added 5 ml of carbon disulfide and 20 ml of ethanol, and
the mixture was heated at 80.degree. C. for 12 hr. After cooling,
the reaction mixture was concentrated in vacuo, the obtained
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=1:1), and the product was dried to yield 346
mg of 5,6-difluorobenzimidazole-2-thiol (65% yield in two
processes).
[0120] Subsequently, 93.1 mg of 5,6-difluorobenzimidazole-2-thiol
(0.5 mmol) was dissolved in 2 ml of N,N-dimethylformamide, and the
solution was heated at 80.degree. C. for 12 hr after the addition
of 104 .mu.l of triethylamine and 117 mg of ethyl 4-bromobutyrate.
The reaction mixture was cooled, water was added, the mixture was
extracted with diethyl ether, and the organic layer was
concentrated in vacuo. The residue was purified by preparative thin
layer chromatography (hexane-ethyl acetate=1:1), and the product
was collected and dried to yield 113 mg of
4-(5,6-difluorobenzimidazole-2-ylthio)butyric acid ethyl ester (75%
yield).
[0121] Subsequently, 55 mg of
4-(5,6-difluorobenzimidazole-2-ylthio)butyri- c acid ethyl ester
was dissolved in 2 ml of N,N-dimethylformamide, to the solution
were added 38 mg of potassium carbonate (0.296 mmol) and 49 mg of
1-chloromethylnaphthalene (0.276 mmol), and the mixture was heated
at 80.degree. C. for 3 hr. The reaction mixture was cooled to room
temperature, and after the addition of water, it was extracted with
diethyl ether. The organic layer was dehydrated over magnesium
sulfate and concentrated in vacuo, the residue was purified by
preparative thin layer chromatography (hexane-ethyl acetate=2:1),
and the product was collected and dried to yield 66 mg of
4-(1-((1-naphthyl)methyl)-5,6-diflu-
orobenzimidazole-2-ylthio)butyric acid ethyl ester (82% yield).
[0122] Successively, 66 mg of
4-(1-((1-naphthyl)methyl)-5,6-difluorobenzim-
idazole-2-ylthio)butyric acid ethyl ester was dissolved in 3 ml of
methanol, the solution was heated at 50.degree. C. for 2 hr after
the addition of 0.5 ml of 4M aqueous solution of lithium hydroxide.
After 2 hr, the reaction mixture was neutralized with a 6M
hydrochloric acid, and the mixture was extracted with chloroform.
The organic layer was concentrated in vacuo, the residue was dried
to yield 60 mg of
4-(1-((1-naphthyl)methyl)-5,6-difluorobenzimidazole-2-ylthio)butyric
acid (98% yield).
[0123] LC-MS:calculated value=412.11, and the measured value
(M+1).sup.+=413.3
Example 3
[0124] Production of
4-(1-((1-naphthyl)methyl)-5-cyanobenzimidazole-2-ylth- io)butyric
Acid (Compound No. 363)
[0125] [Process 1]
[0126] 979 mg of 4-cyano-2-nitroaniline (6 mmol) was dissolved in
18 ml of acetonitrile, and the solution was refluxed for 1.5 hr
after the addition of 1.00 ml of anhydrous trifluoroacetic acid
(7.2 mmol). The reaction mixture was cooled to room temperature and
concentrated in vacuo, and the residue was dried to yield 1.396 g
of 4-cyano-2-nitrotrifluoroacetanilide (90% yield).
[0127] [Process 2]
[0128] Subsequently, 3.14 g of 4-cyano-2-nitrotrifluoroacetanilide
(12.1 mmol) was dissolved in 30 ml of tetrahydrofuran, 602.3 mg of
sodium hydride (60%, oily) (15.1 mmol) was added under ice cooling,
and the mixture was stirred at room temperature for 2 hr.
Successively, into the reaction mixture was added 3.35 g of
1-bromonaphthalene (15.2 mmol) at room temperature, and the
resulting mixture was refluxed. After 10 hr reaction, the reaction
mixture was further refluxed for 1.5 hr after the addition of 5 ml
of 5M aqueous solution of sodium hydroxide. The reaction mixture
was cooled to room temperature and dissolved in 300 ml of ethyl
acetate, and the solution was washed with 150 ml of water. The
organic layer was dehydrated with magnesium sulfate and
concentrated in vacuo. To the residue was added a mixed solvent of
hexane-acetone (=2:1), and the formed precipitates were collected
by filtration and dried to yield 2.032 g of orange colored solid of
((1-naphthyl)methyl)(4-cyano-2-nitrophenyl)a- mine (54% yield).
[0129] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 5.01 (2H, d),
6.92 (1H, d), 7.4-7.6 (6H, m), 7.87 (1H, dd), 8.55 (1H, s), 8.74
(1H, s).
[0130] .sup.13C-NMR (100 MHz, CDCl.sub.3, ppm) .delta.: 45.5, 98.3,
115.4, 118.0, 122.5, 125.62, 125.64, 126.5, 127.1, 129.3, 129.4,
130.8, 131.0, 132.0, 132.3, 134.2, 138.0, 147.1.
[0131] [Process 3]
[0132] Successively, to 1.60 g of
((1-naphthyl)methyl)(4-cyano-2-nitrophen- yl)amine (5.27 mmol) were
added 8 ml of ethanol and 8 ml of tetrahydrofuran. Further, 2.9 g
of potassium carbonate (21 mmol) was added, the atmosphere was
substituted with nitrogen, and subsequently, 160 mg of 10%
palladium-carbon was added, and the mixture was heated at
60.degree. C. after the atmosphere was substituted with hydrogen.
After 2 hr, 160 mg of 10% palladium-carbon was further added, and
the mixture was heated at 60.degree. C. after the atmosphere was
substituted with hydrogen. When 4.5 hr had passed from the start of
the reaction, the reaction mixture was cooled to room temperature
and filtered through celite, and the filtrate was concentrated in
vacuo. The obtained residue was purified by silica gel column
chromatography (hexane-acetone=3:1) to yield 1.16 g of colorless
liquid of ((1-naphthyl)methyl)(2-amino-4-cyanop- henyl)amine.
[0133] [Process 4]
[0134] Successively, 0.72 g of
((1-naphthyl)methyl)(2-amino-4-cyanophenyl)- amine (2.63 mmol) was
dissolved in 16 ml of ethanol, and the solution was refluxed after
the addition of 507.5 mg of potassium ethylxanthate (3.17 mmol).
After 17 hr, 504.2 mg of potassium ethylxanthate (3.15 mmol) was
added, and the refluxing was continued. When 40 hr had passed from
the start of the reaction, 0.37 g of active Norit A (manufactured
by Wako Chemical Co. Ltd.) was added, and the mixture was refluxed
for 15 min. The reaction mixture was filtered through celite, 100
ml of hot water of 70.degree. C. was added, the mixture was heated
at 70 .degree. C., and a 40% acetic acid in water was added
dropwise. Further, 1 ml of acetic acid was added, and the mixture
was cooled to room temperature, and stirred for 1 hr. The formed
crystals were collected by filtration and dried to yield 522.6 mg
of 1-((1-naphthyl)methyl)-5-cyanobenzimidazole-2-thiol (63% yield
in two steps).
[0135] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 5.99 (2H, s),
6.90 (1H, dd), 7.03 (1H, d), 7.26 (1H, dt), 7.36 (1H, dt),
7.49-7.59 (4H, m), 7.81 (1H, d), 7.89 (1H, d), 8.16 (1H, d).
[0136] .sup.13C-NMR (100 MHz, CDCl.sub.3, ppm) .delta.: 45.6,
105.6, 113.2, 118.7, 122.6, 124.2, 125.0, 125.9, 126.4, 126.5,
128.3, 128.6, 129.7, 130.5, 131.3, 133.5, 135.7, 171.9.
[0137] [Process 5]
[0138] To 65 mg of the obtained
1-((1-naphthyl)methyl)-5-cyanobenzimidazol- e-2-thiol (0.2 mmol)
were added 41 mg of potassium carbonate (0.3 mmol) and 3 ml of
N,N-dimethylformamide, and the mixture was heated and stirred at
80.degree. C. for 10 hr after the addition of 50 mg of ethyl
4-bromo-n-butyrate (0.26 mmod). Then, the reaction mixture was
extracted with diethyl ether after the addition of water, and the
organic layer was concentrated in vacuo. The obtained residue was
purified by a silica gel column chromatography (hexane-ethyl
acetate=3:2) to yield 56 mg of a yellow oily substance of
4-(1-((1-naphthyl)methyl)-5-cyanobenzimidazole-2- -ylthio)butyric
acid ethyl ester (65% yield).
[0139] LC/MS: the calculated value M=429.15, and the measured value
(M+1)+=430.3.
[0140] [Process 6]
[0141] 56 mg of
4-(1-((1-naphthyl)methyl)-5-cyanobenzimidazole-2-ylthio)bu- tyric
acid ethyl ester was dissolved in 5 ml of methanol, and the
solution was heated at 50.degree. for 5 hr after the addition of
0.5 ml of a 4M aqueous solution of lithium hydroxide. After 5 hr,
the reaction mixture was extracted with ethyl acetate after the
neutralization with a 6M hydrochloric acid. The organic layer was
concentrated in vacuo, the residue was purified by preparative thin
layer chromatography (chloroform-methanol=20:1), and the product
was dried to yield 27 mg of
4-(1-((1-naphthyl)methyl)-5-cyanobenzimidazole-2-ylthio)butyric
acid (53% yield)
[0142] .sup.1H-NMR (400 MHz, CDCl.sub.3, ppm) .delta.: 2.13 (2H,
pentet), 2.45 (2H, t), 3.50 (2H, d), 5.85 (2H, s), 6.68 (1H, d),
7.15 (1H, dd), 7.34 (2H, m), 7.61 (2H, m), 7.82 (1H, d), 7.93 (1H,
d), 7.97 (1H, s), 8.04 (1H, d).
[0143] .sup.13C-NMR (100 MHz, CDCl.sub.3, ppm) .delta.: 24.3, 31.6,
32.4, 45.4, 104.7, 110.1, 119.6, 121.9, 122.3, 123.1, 125.1, 125.3,
126.1, 126.7, 128.5, 128.8, 129.5, 130.1, 133.4, 155.9, 174.3.
Example 4
[0144] Production of
4-(1-((1-naohthyl)methyl)-5-cyanobenzimidazole-2-yl)--
3.3-dimethylbutyric Acid (Compound No. 457)
[0145] To 310 mg of
((1-naphthyl)methyl)(4-cyano-2-nitrophenyl)amine (1.13 mmol) was
added 6 ml of tetrahydrofuran, the mixture was cooled with ice, and
it was stirred at room temperature for 16 hr after the addition of
430 mg of ethyl-(3,3-dimethyl)-glutaryl chloride (2.08 mmol). After
16 hr, the reaction fi mixture was filtered through celite, the
solvent was removed in vacuo, and 6 ml of ethanol and 2 ml of conc.
hydrochloric acid were added to the residue, and the read mixture
was refluxed for 10 hr. The reaction mixture was extracted with
ethyl acetate after its pH value was adjusted to 8 with a saturated
sodium bicarbonate aqueous solution, and the organic layer was
dried over magnesium sulfate. The organic layer was concentrated in
vacuo, and the obtained residue was purified by silica gel column
chromatography (hexane:acetone=2:1) to yield 451.26 mg of a yellow
oily substance of 4-(1-((1-naphthyl)methyl)-5-cyanobenzimidaz-
ole-2-yl)-3,3-dimethylbutyric acid ethyl ester.
[0146] Successively, to the obtained compound were added 2 ml of
tetrahydrofuran, 4 ml of ethanol and 2 ml of a 2M aqueous solution
of sodium hydroxide, and the mixture was stirred at room
temperature. After 2 hr, 2 ml of a 2M aqueous solution of sodium
hydroxide was further added, and the mixture was heated and stirred
at 50.degree. C. After 2 hr, the reaction mixture was cooled and
adjusted to pH=3 with a saturated citric acid aqueous solution, and
it was extracted with ethyl acetate (40 ml.times.2) after the
addition of 40 ml of water. The organic layer was concentrated in
vacuo, the obtained residue was purified by a preparative thin
layer chromatograph (Art. 13792 manufactured by Merck Co. Ltd.),
and the product was collected to yield 89 mg of
4-(1-((1-naphthyl)methyl)-5-c-
yanobenzimidazole-2-yl)-3,3-dimethylbutyric acid (20% yield in 2
steps).
[0147] LC/MS: the calculated value M=397.18, and the measured value
(M+1)+-398.3
Example 5
[0148] Production of
4-(1-((1-naphthyl)methyl)benzimidazole-2-ylthio)butyr- ic Acid
(Compound No. 121)
[0149] 115.5 g of benzimidazole-2-thiol (0.769 mol) was suspended
in 225 ml of toluene, to the suspension were added 102.2 g of
triethylamine (1.000 mol, 1.3 eq.) and 175.4 g of ethyl
4-bromobutyrate (0.923 mol, 1.2 eq.), and the resulting mixture was
allowed to react at 80.degree. C. for 12 hr. After the reaction,
the reaction mixture was poured into 500 ml of water, and the
mixture was extracted with ethyl acetate of 500 ml and then of 250
ml serially. The combined organic layer was serially washed with
300 ml of water (two times) and with 300 ml of brine, dehydrated
with magnesium sulfate (together with 5 g of active carbon) and
then concentrated in vacuo to give 196 g of a crude product. The
product was recrystalized with 600 ml of diisopropyl ether, the
precipitated crystals were washed with cold diisopropyl ether and
dried to yield 173 g of ethyl 4-(benzimidazole-2-ylthio)butyrate
(85% yield, weakly yellowed white crystal).
[0150] Subsequently, 200 ml of N,N-dimethylformamide was added to
20.2 g of ethyl 4-(benzimidazole-2-ylthio)butyrate (76.2 mmol),
16.1 g of 1-chloromethylnaphthalene (91.4 mmol) and 12.6 g of
potassium carbonate (91.4 mmol), and the mixture was stirred at
80.degree. C. for 5 hr. To the reaction mixture was added 200 ml of
water, the resulting mixture was extracted with ethyl acetate (150
ml.times.3), and the organic layer was washed with water (100
ml.times.3). The organic layer was dried over magnesium sulfate,
the solvent was removed in vacuo, the residue was purified by
silica gel chromatography (hexane:ethyl acetate=9:1) to yield 23.7
g of ethyl 4-(1-((1-naphthyl)methyl)benzimidazole-2-ylthio)butyrate
(77% yield).
[0151] .sup.1H-NMR (270 MHz, CDCl.sub.3, ppm) .delta.: 1.22 (3H, t,
J=7.09 Hz), 2.13 (2H, m), 2.56 (2H, t, J=7.42 Hz), 3.48 (2H, t,
7.09 Hz), 4.11 (2H, q, J=7.09 Hz), 5.80 (2H, s), 6.68 (1H, d,
J=6.10 Hz), 7.05-7.11 (2H, m), 7.20-7.31 (2H, mY, 7.57-7.65 (2H,
m), 7.72-7.80 (2H, m), 7.93 (1H, d, J=7.75 Hz), 8.07 (1H, d, J=8.08
Hz).
[0152] Successively, 23.5 g of ethyl
4-(1-((1-naphthyl)methyl)benzimidazol- e-2-ylthio)butyrate (58.1
mmol) was dissolved in a mixed solvent of 240 ml of THF and 120 ml
of methanol, and the solution was stirred at room temperature over
night after the addition of 29 ml of a 4M aqueous solution of
lithium hydroxide (116 mmol). The reaction mixture was made acidic
by adding a saturated citric acid aqueous solution and extracted
with ethyl acetate (150 ml.times.3), and the organic layer was
washed with water (150 ml.times.3) and dried over magnesium
sulfate. The solvent was removed with a rotary evaporator. The
residue was recrystalized from 900 ml of isopropyl alcohol to yield
20.7 g of 4-(1-((1-naphthyl)methyl)b- enzimidazole-2-ylthio)butyric
acid (95% yield).
[0153] The calculated value=376.12, and the measured value
(M+1).sup.+=377.2.
Example 6
[0154] Production of Sodium
4-(1-((1-naphthyl)methyl)benzimidazole-2-ylthi- o)butyrate (Na salt
of Compound No. 121)
[0155] 1.00 g of
4-(1-((1-naphthyl)methyl)benzimidazole-2-ylthio)butyric acid (2.65
mmol) was suspended in 10 ml of water, and the suspension was
stirred at room temperature over night after the addition of 26.5
ml of a 1M aqueous solution of sodium hydroxide (2.65 mmol). The
reaction mixture was frozen As and lyophilized to yield 981 mg of
4-(1-((1-naphthyl)methyl- )benzimidazole-2-ylthio)butyric acid
sodium salt (93% yield).
[0156] .sup.1H-NMR (270 MHz, DMSO-d.sub.6, ppm) .delta.: 1.83 (2H,
m), 1.98 (2H, m), 3.34 (2H, m), 5.90 (2H, s), 6.55 (1H, d, J=6.76
Hz), 7.08-7.19 (2H, m), 7.27-7.38 (2H, m), 7.61-7.64 (3H, m), 7.84
(1H, d, J=8.41 Hz), 7.99 (1H, d, J=7.75 Hz), 8.24 (1H, d, J=8.08
Hz).
Example 7
[0157] Production of
4-(1-((8-methyl-1-naphthyl)methyl)benzimidazole-2-ylt- hio)butyric
Acid (Compound No. 492)
[0158] 840 mg of 1,8-dimethylnaphthalene (5.11 mmol) was dissolved
in 10 ml of carbon tetrachloride, to the solution were added 890 mg
of NBS (5.0 mmol) and 41 mg of AIBN (0.25 mmol), and the mixture
was stirred at 90.degree. C. for 1 hr. The reaction mixture was
filtered to remove the salt, and the filtrate was treated with a
rotary evaporator to remove the solvent. The formed residue was
purified by silica gel column (hexane) to yield 330 mg of
1-bromomethyl-8-methylnaphthalene (1.4 mmol, 28% yield).
[0159] .sup.1H-NMR(270 MHz, CDCl.sub.3, ppm) .delta.: 3.124 (3H,
s), 5.170 (2H, s), 7.361-7.412 (3H, m), 7.535 (1H, dd), 7.709-7.756
(1H, m), 7.829 (1H, dd).
[0160] Subsequently, to 111 mg of ethyl
4-(benzimidazole-2-ylthio)butyrate (0.42 mmol), 108 mg of
1-bromomethyl-8-methylnaphthalene (0.46 mmol) and 83 mg of
potassium carbonate (0.60 mmol) was added 2.0 ml of
N,N-dimethylformamide, and the mixture was stirred at 80.degree. C.
for 3 hr. The All reaction mixture was filtered to remove the salt,
and the filtrate was treated with a rotary evaporator to remove the
solvent. The formed residue was purified by preparative thin layer
chromatography (ethyl acetate-chloroform=1:8) to yield 149.8 mg of
ethyl 4-(1-((8-methyl-1-naphthyl)methyl)
benzimidazole-2-ylthio)butyrate (0.36 mmol, 86% yield).
[0161] The calculated value M=418.17, and the measured value
(M+1).sup.+=419.1.
[0162] Successively, 149.8 mg of ethyl
4-(1-((8-methyl-1-naphthyl)methyl)b- enzimidazole-2-ylthio)butyrate
(0.36 mmod) was dissolved in a mixed solvent of 5 ml of methanol
and 5 ml of water, to the solution was added 3 ml of a 1M aqueous
solution of sodium hydroxide, and the mixture was stirred at
60.degree. C. for 1 hr. The reaction mixture was adjusted at pH=3
with a saturated aqueous solution of citric acid and extracted with
ethyl acetate. The organic layer was washed with a small amount of
water and dried over magnesium sulfate. The solvent was removed by
a rotary evaporator to yield 159.8 mg of
4-(1-((8-methyl-1-naphthyl)methyl) benzimidazole-2-ylthio) butyric
acid.
[0163] .sup.1H-NMR (270 MHz, CDCl.sub.3, ppm) .delta.: 2.158 (2H,
m), 2.596 (2H, t), 3.066 (3H, s), 3.454 (2H, t), 6.086 (2H, s),
6.471 (1H, d), 7.048 (1H, d), 7.129-7.204 (2H, m), 7.242-7.298 (1H,
m), 7.389-7.435 (2H, m), 7.751-7.793 (3H, m).
[0164] The calculated value M=390.14, and the measured value
(M+1).sup.+=391.1
Example 8
[0165] Production of
4-(1-((8-methyl-1-naphthyl)methyl)-5,6-dimethylbenzim-
idazole-2-ylthio)-butyric Acid (Compound No. 493)
[0166] The titled compound was obtained by employing the same
procedure described in Example 7, but using ethyl
4-(5,6-dimethylbenzimidazole-2-yl- thio)butyrate in the second
process.
[0167] .sup.1H-NMR (270 MHz, CDCl.sub.3, ppm): .delta.: 2.183 (2H,
m), 2.262 (3H, s), 2.355 (3H, s), 2.633 (2H, t), 3.076 (3H, s),
3.435 (1H, t), 6.051 (2H, s), 6.455 (1H, dd), 6.853 (1H, d), 7.193
(2H, t), 7.410 (2H, d), 7.544 (1H, s), 7.742-7.763 (2H, m).
[0168] The calculated value M=418.17, and the measured value
(M+1).sup.+=419.1.
Example 9
[0169] Production of
5-(1-((1-nanhthyl)methyl)benzimidazole-2-ylthio)-4-ox-
o-3,3-dimethylvaleric Acid (Compound No. 494)
[0170]
5-(1-((1-naphthyl)methyl)benzimidazole-2-ylthio)-4-oxo-3,3-dimethyl-
-val eric acid was obtained by employing the same procedure
described in Example 3, but changing the reagents partially as
follows.
[0171] [Process 1]
[0172] 4-cyano-2-nitroaniline.fwdarw.2-nitroaniline.
[0173] [Process 5]
[0174] ethyl 4-bromo-n-butyrate.fwdarw.ethyl
5-bromo-4-oxo-3,3-dimethylval- erate.
[0175] [Process 6]
[0176] 4M aqueous solution of lithium hydroxide.fwdarw.1M aqueous
solution of sodium hydroxide.
[0177] LC-MS: the calculated value=432.15, and the measured value
(M+1).sup.+=433.2
Example 10
[0178] Production of
4-(1-((1-naphthyl)methyl)-5-trifluoromethylbenzimidaz-
ole-2-ylthio)butyric Acid (Compound No. 126)
[0179]
4-(1-((1-naphthyl)methyl)-5-trifluoromethylbenzimidazole-2-ylthio)
-butyric acid was obtained by employing the same procedure
described in Example 3, but changing the reagents partially as
follows.
[0180] [Process 1]
[0181]
4-cyano-2-nitroaniline.fwdarw.4-trifluoromethyl-2-nitroaniline.
[0182] [Process 5]
[0183] potassium carbonate.fwdarw.triethyl amine.
[0184] [Process 6]
[0185] 4M aqueous solution of lithium hydroxide.fwdarw.1M aqueous
solution of sodium hydroxide
[0186] LC-MS: the calculated value=444.11, and the measured value
(M+1).sup.+=445.3
Example 11
[0187] Production of
4-(1-((2,5-dimethylphenil)methyl)-5-methoxybenzimidaz-
ole-2-ylthio)butyric Acid (Compound No. 495)
[0188]
4-(1-((2,5-dimethylphenyl)methyl)-5-methoxybenzimidazole-2-ylthio)b-
ut yric acid was obtained by employing the same procedure described
in Example 3, but changing the reagents partially as follows.
[0189] [Process 1]
[0190] 4-cyano-2-nitroaniline.fwdarw.4-methoxy2-nitroaniline
[0191] [Process 2]
[0192] sodium hydroxide.fwdarw.potassium carbonate;
1-bromomethylnaphthalene.fwdarw.2,5-dimethyl-1-chloromethylbenzene
[0193] [Process 6]
[0194] 4M aqueous solution of lithium hydroxide.fwdarw.2M aqueous
solution of sodium hydroxide.
[0195] LC-MS: the calculated value=384.15, and the measured value
(M+1).sup.+=385.3
Example 12
[0196] Production of
4-(1-((2,5-dimethylphenyl)methyl)-5-cyanobenzimidazol-
e-2-ylthio)butyric Acid (Compound No. 337)
[0197]
4-(1-((2,5-dimethylphenyl)methyl)-5-cyanobenzimidazole-2-ylthio)-bu-
tyric acid was obtained by employing the same procedure described
in Example 3, but changing the reagents partially as follows.
[0198] [Process 2]
[0199] sodium hydroxide.fwdarw.potassium carbonate;
1-bromomethylnaphthalene.fwdarw.2,5-dimethyl-1-bromomethylbenzene
[0200] [Process 6]
[0201] 4M aqueous solution of lithium hydroxide.fwdarw.2M aqueous
solution of sodium hydroxide.
[0202] LC-MS: the calculated value=379.14, and the measured value
(M+1).sup.+=380.3.
Example 13
[0203] Production of
4-(1-((1-naphthyl)methyl)-5-ethoxybenzimidazole-2-ylt- hio)butyric
Acid (Compound No. 128)
[0204]
4-(1-((1-naphthyl)methyl)-5-ethoxybenzimidazole-2-ylthio)butyric
acid was obtained by employing the same procedure described in
Example 1, but changing the reagents partially as follows.
[0205] [Process 1]
[0206] 4-methoxy-2-nitroaniline.fwdarw.4-ethoxy-2-nitroaniline
[0207] LC-MS: the calculated value=420.15, and the measured value
(M+1).sup.+=421.3.
Example 14
[0208] Production of
3-(1-((1-naphthyl)methyl)-benzimidazole-2-ylthio)prop- anoic Acid
(Compound No. 496)
[0209] 3-(1-((1-naphthyl)methyl)-benzimidazole-2-ylthio)propanoic
acid was obtained by employing the same procedure described in
Example 3, but changing the reagents partially as follows.
[0210] [Process 1]
[0211] 4-cyano-2-nitroaniline.fwdarw.2-nitroaniline
[0212] [Process 5] ethyl 4-bromo-n-butyrate.fwdarw.ethyl
3-bromo-propanoate
[0213] LC-MS: the calculated value=362.11, and the measured value
(M+1).sup.+=363.3.
Example 15
[0214] Production of
5-(1-((1-naphthyl)methyl)-benzimidazole-2-ylthio)vale- ric Acid
(Compound No 497)
[0215] 5-(1-((1-naphthyl)methyl)-benzimidazole-2-ylthio)valeric
acid was obtained by employing the same procedure described in
Example 3, but changing the reagents partially as follows.
[0216] [Process 1]
[0217] 4-cyano-2-nitroaniline.fwdarw.2-nitroaniline
[0218] [Process 5]
[0219] ethyl 4-bromo-n-butyrate.fwdarw.ethyl 5-bromovalerate
[0220] LC-MS: the calculated value=390.14, and the measured value
(M+1).sup.+=391.3.
Example 16
[0221] Production of
4-(1-((1-naphthyl)methyl)-5.6-dimethylbenzimidazole
-2-ylthio)butyric Acid (Compound No. 129)
[0222]
4-(1-((1-naphthyl)methyl)-5,6-dimethylbenzimidazole-2-ylthio)butyri-
c acid was obtained by employing the same procedure described in
Example 1; however, the reactions were carried out from Process 4
by using a commercially available 2-amino-4,5-dimethylaniline.
[0223] LC-MS: the calculated value=404.16, and the measured value
(M+1).sup.+=405.3.
Example 17
[0224] Production of
4(1-((1-naphthyl)methyl)-5.6-dimethylbenzimidazole-2--
ylsulfonyl)butyric Acid (Compound No. 498)
[0225] 83 mg of ethyl
4-(1-((1-naphthyl)methyl)-5,6-dimethylbenzimidazole--
2-ylthio)butyrate (0.19 mmol) obtained in Process 5 of Example 16
was dissolved in 5 ml of methylene chloride, to the solution was is
added 70 mg of MCPBA (0.40 mmol), and the resulting mixture was
stirred at room temperature for 4 hr. After the finish of the
reaction, the reaction mixture was extracted with chloroform after
the addition of a saturated aqueous solution of sodium
hydrogencarbonate. The organic layer was dried over magnesium
sulfate, and the solvent was removed in vacuo. The obtained residue
was dissolved in 5 ml of methanol, to the solution was added 1 ml
of a 4M aqueous solution of lithium hydroxide, and the mixture was
stirred at room temperature for 4 hr. After adding 6M hydrochloric
acid, the reaction mixture was extracted with chloroform, the
organic layer was dried over magnesium sulfate, and the solvent was
removed in vacuo. The obtained residue was purified by silica gel
chromatography (chloroform:methanol=20:1) to yield 50.2 mg of
4-(1-((1-naphthyl)methyl)--
5,6-dimethylbenzimidazole-2-ylsulfonyl)butyric acid (0.115 mmol,
61% yield in two steps).
[0226] LC-MS: the calculated value=436.15, and the measured value
(M+1).sup.+=437.2.
Example 18
[0227] Production of
4-(1-((2,5-dimethylphenyl)methyl)-7-azabenzimidazole
-2-ylthio)butyric Acid
[0228]
4-(1-((2,5-dimethylphenyl)methyl)-7-azabenzimidazol-2-ylthio)butyri-
c acid was obtained by employing the same procedure described in
Example 1, but changing the reagents partially as follows.
[0229] [Process 1]
[0230] 4-methoxy-2-nitroanlline.fwdarw.2-amino-3-nitropyridine.
[0231] LC-MS: the calculated value=355.14, and the measured value
(M+1).sup.+=356.2
Example 19
[0232] Preparation of Recombinant Human Mast Cell Chymase
[0233] A recombinant pro-type human mast cell chymase was prepared
according to the report by Urata et al., Journal of Biological
Chemistry 17173, Vol. 266 (1991). That is, the product was purified
from the supernatant of the culture broth of insect cell (Tn 5)
infected with a recombinant baculovirus containing a cDNA encoding
a human mast cell chymase by heparin sepharose (manufactured by
Pharmacia Co.). The obtained chymase was further activated
according to the report of Murakami et al., Journal of Biological
Chemistry, 2218, Vol. 270 (1995), and then it was purified by
heparin sepharose to yield an active-type human mast cell
chymase.
Example 20
[0234] Measuring the Inhibition of Enzyme Activity of Recombinant
Human Mast Cell Chymase
[0235] To 50 .mu.l of buffer A (0.5 to 3.0 M NaCl, 50 mM tris-HCl,
pH 8.0) containing 1 to 5 ng of the active-type human mast cell
chymase obtained by Example 19 was added 2 .mu.l of a DMSO solution
containing a compound of the present invention, and the mixture was
made to react at room temperature for 5 min after the addition of
50 .mu.l of the buffer A containing 0.5 mM of
succinyl-alanyl-histidyl-prolyl-phenylalanylparanitr- oanilide
(Bacchem Co.) as a substrate. The inhibition activity was
determined by measuring the variation of the absorption at 405 nM
with the passage of time.
[0236] As a result, an inhibition activity of IC.sub.50=1 to 10 nM
was observed in each of Compounds No. 121, 127, 129, 492 and 493.
An inhibition activity of IC.sub.50=10 to 100 nM was observed in
each of Compounds No. 126, 128, 131, 337, 363, 494, 495, 496, 497
and 498.
[0237] As shown above, a benzimidazole derivative of the present
invention exhibits a strong chymase inhibition activity. It has
become clear that the compound is therefore clinically applicable
as an inhibitor against human chymase activity which is useful for
the prevention and/or treatment of various kinds of diseases
associated with a human chymase.
Example 21
[0238] Measuring Blood Concentration in Forced Oral Administration
into Rat Stomach
[0239] By using a SD male rat, a compound having the compound
number of 121, 127 or 363 was forcedly administered at a dose of 30
mg/kg into the stomach under starvation, and blood samples were
taken out at 30 min, 1 hr, 2 hr, 4 hr and 8 hr after the
administration. Directly after the collection of the blood samples,
the serum component was separated, the compound of the present
invention was extracted by a general method of solid extraction,
and the obtained sample was subjected to HPLC analysis by using an
ODS column to measured the amount of the unchanged compound. The
results are shown in the following table.
2 AUC (extrapolation) Compound No. (.mu.g .times. hr/mL) Cmax
(.mu.g/mL) 121 226 122 127 181 76 363 182 77
[0240] It has become clear from the result shown above that the
compounds of the present invention belong to a pharmaco-kinetically
excellent group. Especially, the group of the compounds whose B is
--CH.sub.2CH.sub.2CH.sub.2-- is pharmaco-kinetically excellent.
Example 22
[0241] In vitro Metabolic Test Using Hepatic Microsome (Ms)
[0242] Measuring Method
[0243] Reaction Solution Composition and Reaction Conditions
3 Composition and Operation Note Amount of Name Final Reaction
Composition of Reagent Concentration Solution A Buffer phosphate
buffer 0.1 M 0.5 mL (pH 7.4) Chelating EDTA 1.0 mM Agent NADPH
magnesium chloride 3.0 mM Generation G6P 5.0 mM System G6PDH 1.0 IU
Enzyme hepatic microsome 1.0 mg/mL Substrate substrate (test 5.0
.mu.M compound) Reaction NADPH 1.0 mM Starting Liquid Reaction
37.degree. C. incubation (water bath, Conditions vibration)
reaction time: 0, 2, 5, 10 and 30 min Reaction acetonitrile 3 times
Stopping the Liquid amount of (Extraction reaction Liquid) liquid
Protein 3000 rpm, 10 min centrifugation Removal collect
supernatant, and solvent removal by rotary evaporator Liquid of
redissolution in moving phase liquid of Redissolution analytical
HPLC Analysis detect the peak of unchanged body in HPLC by UV
detector A: composition of reconstruction system
[0244] Method for Calculating MR
[0245] Letting the amount of the unchanged body at the initial
concentration (reaction time 0 min) 100%, the speed of metabolism
is determined from the amount of the decrease of the unchanged body
at each reaction time, and the maximum speed of metabolism (MR) is
evaluated.
MR=(the substrate concentration at reaction time 0 min-the
substance concentration after the reaction).div.reaction
time.div.protein concentration (nmol/min/mg-protein)
[0246] Following measurement results were obtained by this
method.
4 Remaining Rate (%) of Compound No. MR Substrate at 30 min 121
0.235 56.6 127 0.190 21.6 363 0.147 57.6
[0247] From the above results, it has become clear that compounds
of the present invention belong to a group which is stable in
metabolism. Especially, the group of the compounds having B of
--CH.sub.2CH.sub.2CH.sub.2-- is stable in metabolism.
[0248] Industrial Field of Application
[0249] Benzimidazole derivatives or their salts, which are active
ingredients of inhibitors against human chymase activity of the
present invention, exhibit strong human chymase inhibiting
activity. Accordingly, the inhibiting agent against human chymase
activity of the present invention can be clinically applicable as a
preventing agent and/or a treating agent for various diseases
associated with human chymase.
* * * * *